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{{pp-move-indef}}{{Short description|Semi-autonomous, self-replicating organelle that occurs in varying numbers, shapes, and sizes in the cytoplasm of virtually all eukaryotic cells; the site of tissue respiration}}(File:Mitochondria, mammalian lung - TEM.jpg|thumb|295px|right|Two mitochondria from mammalian lung tissue displaying their matrix and membranes as shown by electron microscopy){{Cell biology|animalcell=yes|mitochondrion=yes}}The mitochondrion (plural mitochondria) is a double-membrane-bound organelle found in most eukaryotic organisms. Some cells in some multicellular organisms may, however, lack them (for example, mature mammalian red blood cells). A number of unicellular organisms, such as microsporidia, parabasalids, and diplomonads, have also reduced or transformed their mitochondria into other structures.JOURNAL, Henze K, Martin W, Evolutionary biology: essence of mitochondria, Nature, 426, 6963, 127–128, November 2003, 14614484, 10.1038/426127a, 2003Natur.426..127H, To date, only one eukaryote, Monocercomonoides, is known to have completely lost its mitochondria. The word mitochondrion comes from the Greek , {{transl|el|mitos}}, "thread", and , {{transl|el|chondrion}}, "granule"DICTIONARY, mitochondria,weblink Online Etymology Dictionary, or "grain-like". Mitochondria generate most of the cell's supply of adenosine triphosphate (ATP), used as a source of chemical energy.BOOK, Campbell, Neil A., Brad, Williamson, Robin J., Heyden, vanc, Biology: Exploring Life, Pearson Prentice Hall, 2006, Boston, Massachusetts,weblink 978-0-13-250882-7, A mitochondrion is thus termed the powerhouse of the cell.Mitochondria are commonly between 0.75 and 3 Î¼m² in areaJOURNAL, Wiemerslage L, Lee D, Quantification of mitochondrial morphology in neurites of dopaminergic neurons using multiple parameters, Journal of Neuroscience Methods, 262, 56–65, March 2016, 26777473, 4775301, 10.1016/j.jneumeth.2016.01.008, but vary considerably in size and structure. Unless specifically stained, they are not visible. In addition to supplying cellular energy, mitochondria are involved in other tasks, such as signaling, cellular differentiation, and cell death, as well as maintaining control of the cell cycle and cell growth. Mitochondrial biogenesis is in turn temporally coordinated with these cellular processes.JOURNAL, Valero T, Mitochondrial biogenesis: pharmacological approaches, Current Pharmaceutical Design, 20, 35, 5507–9, 2014, 24606795, 10.2174/138161282035140911142118, Mitochondrial biogenesis is therefore defined as the process via which cells increase their individual mitochondrial mass [3]. ... Mitochondrial biogenesis occurs by growth and division of pre-existing organelles and is temporally coordinated with cell cycle events [1]., 10454/13341, JOURNAL, Sanchis-Gomar F, García-Giménez JL, Gómez-Cabrera MC, Pallardó FV, Mitochondrial biogenesis in health and disease. Molecular and therapeutic approaches, Current Pharmaceutical Design, 20, 35, 5619–33, 2014, 24606801, 10.2174/1381612820666140306095106, Mitochondrial biogenesis (MB) is the essential mechanism by which cells control the number of mitochondria, Mitochondria have been implicated in several human diseases, including mitochondrial disorders,JOURNAL, Gardner A, Boles RG, Is a 'Mitochondrial Psychiatry' in the Future? A Review, Curr. Psychiatry Rev., 1, 3, 255–271, 2005, 10.2174/157340005774575064, cardiac dysfunction,JOURNAL, Lesnefsky EJ, Moghaddas S, Tandler B, Kerner J, Hoppel CL, Mitochondrial dysfunction in cardiac disease: ischemia--reperfusion, aging, and heart failure, Journal of Molecular and Cellular Cardiology, 33, 6, 1065–89, June 2001, 11444914, 10.1006/jmcc.2001.1378, heart failureJOURNAL, Dorn GW, Vega RB, Kelly DP, Mitochondrial biogenesis and dynamics in the developing and diseased heart, Genes & Development, 29, 19, 1981–91, October 2015, 26443844, 4604339, 10.1101/gad.269894.115, and autism.JOURNAL, Griffiths KK, Levy RJ, Evidence of Mitochondrial Dysfunction in Autism: Biochemical Links, Genetic-Based Associations, and Non-Energy-Related Mechanisms, Oxidative Medicine and Cellular Longevity, 2017, 4314025, 2017, 28630658, 5467355, 10.1155/2017/4314025, The number of mitochondria in a cell can vary widely by organism, tissue, and cell type. For instance, red blood cells have no mitochondria, whereas liver cells can have more than 2000.BOOK, Alberts, Bruce, Alexander, Johnson, Julian, Lewis, Martin, Raff, Keith, Roberts, Peter, Walter, vanc, 1994, Molecular Biology of the Cell, Garland Publishing Inc., New York, 978-0-8153-3218-3, BOOK, Voet, Donald, Judith G., Voet, Charlotte W., Pratt, vanc, Fundamentals of Biochemistry, 2nd, John Wiley and Sons, Inc., 2006, 547, 556, 978-0-471-21495-3,weblink The organelle is composed of compartments that carry out specialized functions. These compartments or regions include the outer membrane, the intermembrane space, the inner membrane, and the cristae and matrix.Although most of a cell's DNA is contained in the cell nucleus, the mitochondrion has its own independent genome that shows substantial similarity to bacterial genomes.JOURNAL, Andersson SG, Karlberg O, Canbäck B, Kurland CG, On the origin of mitochondria: a genomics perspective, Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 358, 1429, 165–77; discussion 177–9, January 2003, 12594925, 1693097, 10.1098/rstb.2002.1193, Mitochondrial proteins (proteins transcribed from mitochondrial DNA) vary depending on the tissue and the species. In humans, 615 distinct types of protein have been identified from cardiac mitochondria,JOURNAL, Taylor SW, Fahy E, Zhang B, Glenn GM, Warnock DE, Wiley S, Murphy AN, Gaucher SP, Capaldi RA, Gibson BW, Ghosh SS, Characterization of the human heart mitochondrial proteome, Nature Biotechnology, 21, 3, 281–6, March 2003, 12592411, 10.1038/nbt793, whereas in rats, 940 proteins have been reported.JOURNAL, Zhang J, Li X, Mueller M, Wang Y, Zong C, Deng N, Vondriska TM, Liem DA, Yang JI, Korge P, Honda H, Weiss JN, Apweiler R, Ping P, Systematic characterization of the murine mitochondrial proteome using functionally validated cardiac mitochondria, Proteomics, 8, 8, 1564–75, April 2008, 18348319, 2799225, 10.1002/pmic.200700851, The mitochondrial proteome is thought to be dynamically regulated.JOURNAL, Zhang J, Liem DA, Mueller M, Wang Y, Zong C, Deng N, Vondriska TM, Korge P, Drews O, Maclellan WR, Honda H, Weiss JN, Apweiler R, Ping P, Altered proteome biology of cardiac mitochondria under stress conditions, Journal of Proteome Research, 7, 6, 2204–14, June 2008, 18484766, 3805274, 10.1021/pr070371f,


The first observations of intracellular structures that probably represented mitochondria were published in the 1840s.JOURNAL, Ernster L, Schatz G, Mitochondria: a historical review, The Journal of Cell Biology, 91, 3 Pt 2, 227s–255s, December 1981, 7033239, 2112799, 10.1083/jcb.91.3.227s, Richard Altmann, in 1890, established them as cell organelles and called them "bioblasts".Altmann, R. 1890 . Die Elementarorganismen und ihre Beziehungen zu den Zellen. Veit, Leipzig, weblink. The term "mitochondria" was coined by Carl Benda in 1898.JOURNAL, Benda C, 1898, Ueber die Spermatogenese der Vertebraten und höherer Evertebraten. II. Theil: Die Histiogenese der Spermien., Arch. Anal. Physiol., 393–398,weblink Leonor Michaelis discovered that Janus green can be used as a supravital stain for mitochondria in 1900. In 1904, Friedrich Meves, made the first recorded observation of mitochondria in plants in cells of the white waterlily, Nymphaea albaErnster's citation JOURNAL, Meves, Friedrich, May 1908, Die Chondriosomen als Träger erblicher Anlagen. Cytologische Studien am Hühnerembryo, Archiv für Mikroskopische Anatomie, 72, 1, 816–867, 10.1007/BF02982402,weblink is wrong, correct citation is JOURNAL, Meves, Friedrich, 1904, Über das Vorkommen von Mitochondrien bezw. Chondromiten in Pflanzenzellen, Ber. Dtsch. Bot. Ges., 22, 284–286, , cited in Meves' 1908 paper and in JOURNAL, Schmidt, Ernst Willy, 1913, Pflanzliche Mitochondrien, Progressus Rei Botanicae, 4, 164–183,weblink 21 September 2012, , with confirmation of Nymphaea alba and in 1908, along with Claudius Regaud, suggested that they contain proteins and lipids. Benjamin F. Kingsbury, in 1912, first related them with cell respiration, but almost exclusively based on morphological observations. In 1913, particles from extracts of guinea-pig liver were linked to respiration by Otto Heinrich Warburg, which he called "grana". Warburg and Heinrich Otto Wieland, who had also postulated a similar particle mechanism, disagreed on the chemical nature of the respiration. It was not until 1925, when David Keilin discovered cytochromes, that the respiratory chain was described.In 1939, experiments using minced muscle cells demonstrated that cellular respiration using one oxygen atom can form two adenosine triphosphate (ATP) molecules, and, in 1941, the concept of the phosphate bonds of ATP being a form of energy in cellular metabolism was developed by Fritz Albert Lipmann. In the following years, the mechanism behind cellular respiration was further elaborated, although its link to the mitochondria was not known. The introduction of tissue fractionation by Albert Claude allowed mitochondria to be isolated from other cell fractions and biochemical analysis to be conducted on them alone. In 1946, he concluded that cytochrome oxidase and other enzymes responsible for the respiratory chain were isolated to the mitochondria. Eugene Kennedy and Albert Lehninger discovered in 1948 that mitochondria are the site of oxidative phosphorylation in eukaryotes. Over time, the fractionation method was further developed, improving the quality of the mitochondria isolated, and other elements of cell respiration were determined to occur in the mitochondria.The first high-resolution electron micrographs appeared in 1952, replacing the Janus Green stains as the preferred way of visualising the mitochondria. This led to a more detailed analysis of the structure of the mitochondria, including confirmation that they were surrounded by a membrane. It also showed a second membrane inside the mitochondria that folded up in ridges dividing up the inner chamber and that the size and shape of the mitochondria varied from cell to cell.The popular term "powerhouse of the cell" was coined by Philip Siekevitz in 1957.JOURNAL, Siekevitz P, Powerhouse of the cell, Scientific American, 1957, 197, 131–140, 10.1038/scientificamerican0757-131, 1, 1957SciAm.197a.131S, In 1967, it was discovered that mitochondria contained ribosomes.JOURNAL, Martin WF, Garg S, Zimorski V, Endosymbiotic theories for eukaryote origin, Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 370, 1678, 20140330, September 2015, 26323761, 4571569, 10.1098/rstb.2014.0330, In 1968, methods were developed for mapping the mitochondrial genes, with the genetic and physical map of yeast mitochondrial DNA being completed in 1976.

Origin and evolution

There are two hypotheses about the origin of mitochondria: endosymbiotic and autogenous. The endosymbiotic hypothesis suggests that mitochondria were originally prokaryotic cells, capable of implementing oxidative mechanisms that were not possible for eukaryotic cells; they became endosymbionts living inside the eukaryote.BOOK, Margulis, Lynn, Sagan, Dorion, vanc, Origins of Sex. Three Billion Years of Genetic Recombination., New Haven, Yale University Press, 1986, 69–71, 87, 978-0-300-03340-3,weblink In the autogenous hypothesis, mitochondria were born by splitting off a portion of DNA from the nucleus of the eukaryotic cell at the time of divergence with the prokaryotes; this DNA portion would have been enclosed by membranes, which could not be crossed by proteins. Since mitochondria have many features in common with bacteria, the endosymbiotic hypothesis is more widely accepted.BOOK, William F., Martin, Miklós, Müller, vanc, Origin of mitochondria and hydrogenosomes, Springer Verlag, Heidelberg, 2007, A mitochondrion contains DNA, which is organized as several copies of a single, usually circular chromosome. This mitochondrial chromosome contains genes for redox proteins, such as those of the respiratory chain. The CoRR hypothesis proposes that this co-location is required for redox regulation. The mitochondrial genome codes for some RNAs of ribosomes, and the 22 tRNAs necessary for the translation of mRNAs into protein. The circular structure is also found in prokaryotes. The proto-mitochondrion was probably closely related to the Rickettsia.JOURNAL, Emelyanov VV, Mitochondrial connection to the origin of the eukaryotic cell, European Journal of Biochemistry, 270, 8, 1599–1618, April 2003, 12694174, 10.1046/j.1432-1033.2003.03499.x, JOURNAL, Müller M, Martin W, The genome of Rickettsia prowazekii and some thoughts on the origin of mitochondria and hydrogenosomes, BioEssays, 21, 5, 377–381, May 1999, 10376009, 10.1002/(sici)1521-1878(199905);2-w,weblink However, the exact relationship of the ancestor of mitochondria to the alphaproteobacteria and whether the mitochondrion was formed at the same time or after the nucleus, remains controversial.JOURNAL, Gray MW, Burger G, Lang BF, Mitochondrial evolution, Science, 283, 5407, 1476–1481, March 1999, 10066161, 10.1126/science.283.5407.1476, 3428767, 1999Sci...283.1476G, For example, it has been suggested that the SAR11 clade of bacteria shares a relatively recent common ancestor with the mitochondria,JOURNAL, Thrash JC, Boyd A, Huggett MJ, Grote J, Carini P, Yoder RJ, Robbertse B, Spatafora JW, Rappé MS, Giovannoni SJ, Phylogenomic evidence for a common ancestor of mitochondria and the SAR11 clade, En, Scientific Reports, 1, 1, 13, 2011-06-14, 22355532, 3216501, 10.1038/srep00013, 2011NatSR...1E..13T, while phylogenomic analyses indicate that mitochondria evolved from a proteobacteria lineage that branched off before the divergence of all sampled alphaproteobacteria.JOURNAL, Martijn J, Vosseberg J, Guy L, Offre P, Ettema TJ, Deep mitochondrial origin outside the sampled alphaproteobacteria, Nature, 557, 7703, 101–105, April 2018, 29695865, 10.1038/s41586-018-0059-5, 2018Natur.557..101M, {{Rickettsialesphylogeny}}The ribosomes coded for by the mitochondrial DNA are similar to those from bacteria in size and structure.JOURNAL, O'Brien TW, Properties of human mitochondrial ribosomes, IUBMB Life, 55, 9, 505–513, September 2003, 14658756, 10.1080/15216540310001626610, They closely resemble the bacterial 70S ribosome and not the 80S cytoplasmic ribosomes, which are coded for by nuclear DNA.The endosymbiotic relationship of mitochondria with their host cells was popularized by Lynn Margulis.JOURNAL, Sagan L, On the origin of mitosing cells, Journal of Theoretical Biology, 14, 3, 255–274, March 1967, 11541392, 10.1016/0022-5193(67)90079-3, The endosymbiotic hypothesis suggests that mitochondria descended from bacteria that somehow survived endocytosis by another cell, and became incorporated into the cytoplasm. The ability of these bacteria to conduct respiration in host cells that had relied on glycolysis and fermentation would have provided a considerable evolutionary advantage. This symbiotic relationship probably developed 1.7 to 2 billion years ago.JOURNAL, Emelyanov VV, Rickettsiaceae, rickettsia-like endosymbionts, and the origin of mitochondria, Bioscience Reports, 21, 1, 1–17, February 2001, 11508688, 10.1023/A:1010409415723, JOURNAL, Feng DF, Cho G, Doolittle RF, Determining divergence times with a protein clock: update and reevaluation, Proceedings of the National Academy of Sciences of the United States of America, 94, 24, 13028–13033, November 1997, 9371794, 24257, 10.1073/pnas.94.24.13028, 1997PNAS...9413028F, A few groups of unicellular eukaryotes have only vestigial mitochondria or derived structures: the microsporidians, metamonads, and archamoebae.JOURNAL, Cavalier-Smith T, Archamoebae: the ancestral eukaryotes?, Bio Systems, 25, 1–2, 25–38, 1991, 1854912, 10.1016/0303-2647(91)90010-I, These groups appear as the most primitive eukaryotes on phylogenetic trees constructed using rRNA information, which once suggested that they appeared before the origin of mitochondria. However, this is now known to be an artifact of long-branch attraction—they are derived groups and retain genes or organelles derived from mitochondria (e.g., mitosomes and hydrogenosomes).Monocercomonoides appear to have lost their mitochondria completely and at least some of the mitochondrial functions seem to be carried out by cytoplasmic proteins now.JOURNAL, Karnkowska A, Vacek V, Zubáčová Z, Treitli SC, Petrželková R, Eme L, Novák L, Žárský V, Barlow LD, Herman EK, Soukal P, Hroudová M, Doležal P, Stairs CW, Roger AJ, Eliáš M, Dacks JB, Vlček Č, Hampl V, A Eukaryote without a Mitochondrial Organelle, English, Current Biology, 26, 10, 1274–1284, May 2016, 27185558, 10.1016/j.cub.2016.03.053,


{{plain image|File:Mitochondrion structure.svg|Mitochondrion ultrastructure (interactive diagram) A mitochondrion has a double membrane; the inner one contains its chemiosmotic apparatus and has deep grooves which increase its surface area. While commonly depicted as an "orange sausage with a blob inside of it" (like it is here), mitochondria can take many shapesWEB, Mitochondrion – much more than an energy converter,weblink British Society for Cell Biology, 19 August 2013, and their intermembrane space is quite thin.|500px|right|bottom|triangle|#bd0926|image override={{Mitochondrion structure}}}}A mitochondrion contains outer and inner membranes composed of phospholipid bilayers and proteins. The two membranes have different properties. Because of this double-membraned organization, there are five distinct parts to a mitochondrion. They are:
  1. the outer mitochondrial membrane,
  2. the intermembrane space (the space between the outer and inner membranes),
  3. the inner mitochondrial membrane,
  4. the cristae space (formed by infoldings of the inner membrane), and
  5. the matrix (space within the inner membrane).
Mitochondria stripped of their outer membrane are called mitoplasts.

Outer membrane

The outer mitochondrial membrane, which encloses the entire organelle, is 60 to 75 angstroms (Å) thick. It has a protein-to-phospholipid ratio similar to that of the cell membrane (about 1:1 by weight). It contains large numbers of integral membrane proteins called porins. A major trafficking protein is the pore-forming voltage-dependent anion channel (VDAC). The VDAC is the primary transporter of nucleotides, ions and metabolites between the cytosol and the intermembrane space.JOURNAL, Blachly-Dyson E, Forte M, VDAC channels, IUBMB Life, 52, 3–5, 113–8, September 2001, 11798022, 10.1080/15216540152845902, JOURNAL, Hoogenboom BW, Suda K, Engel A, Fotiadis D, The supramolecular assemblies of voltage-dependent anion channels in the native membrane, Journal of Molecular Biology, 370, 2, 246–55, July 2007, 17524423, 10.1016/j.jmb.2007.04.073, It is formed as a beta barrel that spans the outer membrane, similar to that in the gram-negative bacterial membrane.JOURNAL, Zeth K, Structure and evolution of mitochondrial outer membrane proteins of beta-barrel topology, Biochimica et Biophysica Acta, 1797, 6–7, 1292–9, June 2010, 20450883, 10.1016/j.bbabio.2010.04.019, Larger proteins can enter the mitochondrion if a signaling sequence at their N-terminus binds to a large multisubunit protein called translocase in the outer membrane, which then actively moves them across the membrane.JOURNAL, Herrmann JM, Neupert W, Protein transport into mitochondria, Current Opinion in Microbiology, 3, 2, 210–4, April 2000, 10744987, 10.1016/S1369-5274(00)00077-1,weblink Mitochondrial pro-proteins are imported through specialised translocation complexes.The outer membrane also contains enzymes involved in such diverse activities as the elongation of fatty acids, oxidation of epinephrine, and the degradation of tryptophan. These enzymes include monoamine oxidase, rotenone-insensitive NADH-cytochrome c-reductase, kynurenine hydroxylase and fatty acid Co-A ligase. Disruption of the outer membrane permits proteins in the intermembrane space to leak into the cytosol, leading to certain cell death.JOURNAL, Chipuk JE, Bouchier-Hayes L, Green DR, Mitochondrial outer membrane permeabilization during apoptosis: the innocent bystander scenario, Cell Death and Differentiation, 13, 8, 1396–1402, August 2006, 16710362, 10.1038/sj.cdd.4401963, The mitochondrial outer membrane can associate with the endoplasmic reticulum (ER) membrane, in a structure called MAM (mitochondria-associated ER-membrane). This is important in the ER-mitochondria calcium signaling and is involved in the transfer of lipids between the ER and mitochondria. Outside the outer membrane there are small (diameter: 60Å) particles named sub-units of Parson.

Intermembrane space

The mitochondrial intermembrane space is the space between the outer membrane and the inner membrane. It is also known as perimitochondrial space. Because the outer membrane is freely permeable to small molecules, the concentrations of small molecules, such as ions and sugars, in the intermembrane space is the same as in the cytosol. However, large proteins must have a specific signaling sequence to be transported across the outer membrane, so the protein composition of this space is different from the protein composition of the cytosol. One protein that is localized to the intermembrane space in this way is cytochrome c.

Inner membrane

The inner mitochondrial membrane contains proteins with five types of functions:
  1. Those that perform the redox reactions of oxidative phosphorylation
  2. ATP synthase, which generates ATP in the matrix
  3. Specific transport proteins that regulate metabolite passage into and out of the mitochondrial matrix
  4. Protein import machinery
  5. Mitochondrial fusion and fission protein
It contains more than 151 different polypeptides, and has a very high protein-to-phospholipid ratio (more than 3:1 by weight, which is about 1 protein for 15 phospholipids). The inner membrane is home to around 1/5 of the total protein in a mitochondrion. In addition, the inner membrane is rich in an unusual phospholipid, cardiolipin. This phospholipid was originally discovered in cow hearts in 1942, and is usually characteristic of mitochondrial and bacterial plasma membranes.JOURNAL, McMillin JB, Dowhan W, Cardiolipin and apoptosis, Biochimica et Biophysica Acta, 1585, 2–3, 97–107, December 2002, 12531542, 10.1016/S1388-1981(02)00329-3, Cardiolipin contains four fatty acids rather than two, and may help to make the inner membrane impermeable. Unlike the outer membrane, the inner membrane doesn't contain porins, and is highly impermeable to all molecules. Almost all ions and molecules require special membrane transporters to enter or exit the matrix. Proteins are ferried into the matrix via the translocase of the inner membrane (TIM) complex or via Oxa1. In addition, there is a membrane potential across the inner membrane, formed by the action of the enzymes of the electron transport chain.


(File:MitochondrionCAM.jpg|thumb|250 px|right|Cross-sectional image of cristae in rat liver mitochondrion to demonstrate the likely 3D structure and relationship to the inner membrane)The inner mitochondrial membrane is compartmentalized into numerous cristae, which expand the surface area of the inner mitochondrial membrane, enhancing its ability to produce ATP. For typical liver mitochondria, the area of the inner membrane is about five times as large as the outer membrane. This ratio is variable and mitochondria from cells that have a greater demand for ATP, such as muscle cells, contain even more cristae. These folds are studded with small round bodies known as F1 particles or oxysomes. These are not simple random folds but rather invaginations of the inner membrane, which can affect overall chemiosmotic function.JOURNAL, Mannella CA, Structure and dynamics of the mitochondrial inner membrane cristae, Biochimica et Biophysica Acta, 1763, 5–6, 542–548, 2006, 16730811, 10.1016/j.bbamcr.2006.04.006, One recent mathematical modeling study has suggested that the optical properties of the cristae in filamentous mitochondria may affect the generation and propagation of light within the tissue.JOURNAL, Thar R, Kühl M, Propagation of electromagnetic radiation in mitochondria?, Journal of Theoretical Biology, 230, 2, 261–270, September 2004, 15302557, 10.1016/j.jtbi.2004.05.021,weblink


The matrix is the space enclosed by the inner membrane. It contains about 2/3 of the total protein in a mitochondrion. The matrix is important in the production of ATP with the aid of the ATP synthase contained in the inner membrane. The matrix contains a highly concentrated mixture of hundreds of enzymes, special mitochondrial ribosomes, tRNA, and several copies of the mitochondrial DNA genome. Of the enzymes, the major functions include oxidation of pyruvate and fatty acids, and the citric acid cycle. The DNA molecules are packaged into nucleoids by proteins, one of which is TFAM.JOURNAL, Bogenhagen DF, Mitochondrial DNA nucleoid structure, Biochimica et Biophysica Acta, 1819, 9–10, 914–20, September 2012, 22142616, 10.1016/j.bbagrm.2011.11.005, Mitochondria have their own genetic material, and the machinery to manufacture their own RNAs and proteins (see: protein biosynthesis). A published human mitochondrial DNA sequence revealed 16,569 base pairs encoding 37 genes: 22 tRNA, 2 rRNA, and 13 peptide genes. The 13 mitochondrial peptides in humans are integrated into the inner mitochondrial membrane, along with proteins encoded by genes that reside in the host cell's nucleus.

Mitochondria-associated ER membrane (MAM)

The mitochondria-associated ER membrane (MAM) is another structural element that is increasingly recognized for its critical role in cellular physiology and homeostasis. Once considered a technical snag in cell fractionation techniques, the alleged ER vesicle contaminants that invariably appeared in the mitochondrial fraction have been re-identified as membranous structures derived from the MAM—the interface between mitochondria and the ER.JOURNAL, Rizzuto R, Marchi S, Bonora M, Aguiari P, Bononi A, De Stefani D, Giorgi C, Leo S, Rimessi A, Siviero R, Zecchini E, Pinton P, Ca(2+) transfer from the ER to mitochondria: when, how and why, Biochimica et Biophysica Acta, 1787, 11, 1342–1351, November 2009, 19341702, 2730423, 10.1016/j.bbabio.2009.03.015, Physical coupling between these two organelles had previously been observed in electron micrographs and has more recently been probed with fluorescence microscopy. Such studies estimate that at the MAM, which may comprise up to 20% of the mitochondrial outer membrane, the ER and mitochondria are separated by a mere 10–25 nm and held together by protein tethering complexes.JOURNAL, Hayashi T, Rizzuto R, Hajnoczky G, Su TP, MAM: more than just a housekeeper, Trends in Cell Biology, 19, 2, 81–88, February 2009, 19144519, 2750097, 10.1016/j.tcb.2008.12.002, JOURNAL, de Brito OM, Scorrano L, An intimate liaison: spatial organization of the endoplasmic reticulum-mitochondria relationship, The EMBO Journal, 29, 16, 2715–2723, August 2010, 20717141, 2924651, 10.1038/emboj.2010.177, Purified MAM from subcellular fractionation has been shown to be enriched in enzymes involved in phospholipid exchange, in addition to channels associated with Ca2+ signaling. These hints of a prominent role for the MAM in the regulation of cellular lipid stores and signal transduction have been borne out, with significant implications for mitochondrial-associated cellular phenomena, as discussed below. Not only has the MAM provided insight into the mechanistic basis underlying such physiological processes as intrinsic apoptosis and the propagation of calcium signaling, but it also favors a more refined view of the mitochondria. Though often seen as static, isolated 'powerhouses' hijacked for cellular metabolism through an ancient endosymbiotic event, the evolution of the MAM underscores the extent to which mitochondria have been integrated into overall cellular physiology, with intimate physical and functional coupling to the endomembrane system.

Phospholipid transfer

The MAM is enriched in enzymes involved in lipid biosynthesis, such as phosphatidylserine synthase on the ER face and phosphatidylserine decarboxylase on the mitochondrial face.JOURNAL, Vance JE, Shiao YJ, Intracellular trafficking of phospholipids: import of phosphatidylserine into mitochondria, Anticancer Research, 16, 3B, 1333–1339, 1996, 8694499, JOURNAL, Lebiedzinska M, Szabadkai G, Jones AW, Duszynski J, Wieckowski MR, Interactions between the endoplasmic reticulum, mitochondria, plasma membrane and other subcellular organelles, The International Journal of Biochemistry & Cell Biology, 41, 10, 1805–1816, October 2009, 19703651, 10.1016/j.biocel.2009.02.017, Because mitochondria are dynamic organelles constantly undergoing fission and fusion events, they require a constant and well-regulated supply of phospholipids for membrane integrity.JOURNAL, Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G, Stiles L, Haigh SE, Katz S, Las G, Alroy J, Wu M, Py BF, Yuan J, Deeney JT, Corkey BE, Shirihai OS, Fission and selective fusion govern mitochondrial segregation and elimination by autophagy, The EMBO Journal, 27, 2, 433–446, January 2008, 18200046, 2234339, 10.1038/sj.emboj.7601963, JOURNAL, Osman C, Voelker DR, Langer T, Making heads or tails of phospholipids in mitochondria, The Journal of Cell Biology, 192, 1, 7–16, January 2011, 21220505, 3019561, 10.1083/jcb.201006159, But mitochondria are not only a destination for the phospholipids they finish synthesis of; rather, this organelle also plays a role in inter-organelle trafficking of the intermediates and products of phospholipid biosynthetic pathways, ceramide and cholesterol metabolism, and glycosphingolipid anabolism.Such trafficking capacity depends on the MAM, which has been shown to facilitate transfer of lipid intermediates between organelles. In contrast to the standard vesicular mechanism of lipid transfer, evidence indicates that the physical proximity of the ER and mitochondrial membranes at the MAM allows for lipid flipping between opposed bilayers. Despite this unusual and seemingly energetically unfavorable mechanism, such transport does not require ATP. Instead, in yeast, it has been shown to be dependent on a multiprotein tethering structure termed the ER-mitochondria encounter structure, or ERMES, although it remains unclear whether this structure directly mediates lipid transfer or is required to keep the membranes in sufficiently close proximity to lower the energy barrier for lipid flipping.JOURNAL, Kornmann B, Currie E, Collins SR, Schuldiner M, Nunnari J, Weissman JS, Walter P, An ER-mitochondria tethering complex revealed by a synthetic biology screen, Science, 325, 5939, 477–481, July 2009, 19556461, 2933203, 10.1126/science.1175088, 2009Sci...325..477K, The MAM may also be part of the secretory pathway, in addition to its role in intracellular lipid trafficking. In particular, the MAM appears to be an intermediate destination between the rough ER and the Golgi in the pathway that leads to very-low-density lipoprotein, or VLDL, assembly and secretion.JOURNAL, Rusiñol AE, Cui Z, Chen MH, Vance JE, A unique mitochondria-associated membrane fraction from rat liver has a high capacity for lipid synthesis and contains pre-Golgi secretory proteins including nascent lipoproteins, The Journal of Biological Chemistry, 269, 44, 27494–27502, November 1994, 7961664, The MAM thus serves as a critical metabolic and trafficking hub in lipid metabolism.

Calcium signaling

A critical role for the ER in calcium signaling was acknowledged before such a role for the mitochondria was widely accepted, in part because the low affinity of Ca2+ channels localized to the outer mitochondrial membrane seemed to contradict this organelle's purported responsiveness to changes in intracellular Ca2+ flux.JOURNAL, Santulli G, Marks AR, Essential Roles of Intracellular Calcium Release Channels in Muscle, Brain, Metabolism, and Aging, Current Molecular Pharmacology, 8, 2, 206–222, 2015, 25966694, 10.2174/1874467208666150507105105, But the presence of the MAM resolves this apparent contradiction: the close physical association between the two organelles results in Ca2+ microdomains at contact points that facilitate efficient Ca2+ transmission from the ER to the mitochondria. Transmission occurs in response to so-called "Ca2+ puffs" generated by spontaneous clustering and activation of IP3R, a canonical ER membrane Ca2+ channel.The fate of these puffs—in particular, whether they remain restricted to isolated locales or integrated into Ca2+ waves for propagation throughout the cell—is determined in large part by MAM dynamics. Although reuptake of Ca2+ by the ER (concomitant with its release) modulates the intensity of the puffs, thus insulating mitochondria to a certain degree from high Ca2+ exposure, the MAM often serves as a firewall that essentially buffers Ca2+ puffs by acting as a sink into which free ions released into the cytosol can be funneled.JOURNAL, Kopach O, Kruglikov I, Pivneva T, Voitenko N, Fedirko N, Functional coupling between ryanodine receptors, mitochondria and Ca(2+) ATPases in rat submandibular acinar cells, Cell Calcium, 43, 5, 469–481, May 2008, 17889347, 10.1016/j.ceca.2007.08.001, JOURNAL, Csordás G, Hajnóczky G, Sorting of calcium signals at the junctions of endoplasmic reticulum and mitochondria, Cell Calcium, 29, 4, 249–262, April 2001, 11243933, 10.1054/ceca.2000.0191, This Ca2+ tunneling occurs through the low-affinity Ca2+ receptor VDAC1, which recently has been shown to be physically tethered to the IP3R clusters on the ER membrane and enriched at the MAM.JOURNAL, Decuypere JP, Monaco G, Bultynck G, Missiaen L, De Smedt H, Parys JB, The IP(3) receptor-mitochondria connection in apoptosis and autophagy, Biochimica et Biophysica Acta, 1813, 5, 1003–1013, May 2011, 21146562, 10.1016/j.bbamcr.2010.11.023, The ability of mitochondria to serve as a Ca2+ sink is a result of the electrochemical gradient generated during oxidative phosphorylation, which makes tunneling of the cation an exergonic process. Normal, mild calcium influx from cytosol into the mitochondrial matrix causes transient depolarization that is corrected by pumping out protons.But transmission of Ca2+ is not unidirectional; rather, it is a two-way street. The properties of the Ca2+ pump SERCA and the channel IP3R present on the ER membrane facilitate feedback regulation coordinated by MAM function. In particular, the clearance of Ca2+ by the MAM allows for spatio-temporal patterning of Ca2+ signaling because Ca2+ alters IP3R activity in a biphasic manner. SERCA is likewise affected by mitochondrial feedback: uptake of Ca2+ by the MAM stimulates ATP production, thus providing energy that enables SERCA to reload the ER with Ca2+ for continued Ca2+ efflux at the MAM. Thus, the MAM is not a passive buffer for Ca2+ puffs; rather it helps modulate further Ca2+ signaling through feedback loops that affect ER dynamics.Regulating ER release of Ca2+ at the MAM is especially critical because only a certain window of Ca2+ uptake sustains the mitochondria, and consequently the cell, at homeostasis. Sufficient intraorganelle Ca2+ signaling is required to stimulate metabolism by activating dehydrogenase enzymes critical to flux through the citric acid cycle.JOURNAL, Hajnóczky G, Csordás G, Yi M, Old players in a new role: mitochondria-associated membranes, VDAC, and ryanodine receptors as contributors to calcium signal propagation from endoplasmic reticulum to the mitochondria, Cell Calcium, 32, 5–6, 363–377, 2011, 12543096, 10.1016/S0143416002001872, However, once Ca2+ signaling in the mitochondria passes a certain threshold, it stimulates the intrinsic pathway of apoptosis in part by collapsing the mitochondrial membrane potential required for metabolism. Studies examining the role of pro- and anti-apoptotic factors support this model; for example, the anti-apoptotic factor Bcl-2 has been shown to interact with IP3Rs to reduce Ca2+ filling of the ER, leading to reduced efflux at the MAM and preventing collapse of the mitochondrial membrane potential post-apoptotic stimuli. Given the need for such fine regulation of Ca2+ signaling, it is perhaps unsurprising that dysregulated mitochondrial Ca2+ has been implicated in several neurodegenerative diseases, while the catalogue of tumor suppressors includes a few that are enriched at the MAM.

Molecular basis for tethering

Recent advances in the identification of the tethers between the mitochondrial and ER membranes suggest that the scaffolding function of the molecular elements involved is secondary to other, non-structural functions. In yeast, ERMES, a multiprotein complex of interacting ER- and mitochondrial-resident membrane proteins, is required for lipid transfer at the MAM and exemplifies this principle. One of its components, for example, is also a constituent of the protein complex required for insertion of transmembrane beta-barrel proteins into the lipid bilayer. However, a homologue of the ERMES complex has not yet been identified in mammalian cells. Other proteins implicated in scaffolding likewise have functions independent of structural tethering at the MAM; for example, ER-resident and mitochondrial-resident mitofusins form heterocomplexes that regulate the number of inter-organelle contact sites, although mitofusins were first identified for their role in fission and fusion events between individual mitochondria. Glucose-related protein 75 (grp75) is another dual-function protein. In addition to the matrix pool of grp75, a portion serves as a chaperone that physically links the mitochondrial and ER Ca2+ channels VDAC and IP3R for efficient Ca2+ transmission at the MAM. Another potential tether is Sigma-1R, a non-opioid receptor whose stabilization of ER-resident IP3R may preserve communication at the MAM during the metabolic stress response.JOURNAL, Marriott KS, Prasad M, Thapliyal V, Bose HS, σ-1 receptor at the mitochondrial-associated endoplasmic reticulum membrane is responsible for mitochondrial metabolic regulation, The Journal of Pharmacology and Experimental Therapeutics, 343, 3, 578–586, December 2012, 22923735, 3500540, 10.1124/jpet.112.198168, JOURNAL, Hayashi T, Su TP, Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival, Cell, 131, 3, 596–610, November 2007, 17981125, 10.1016/j.cell.2007.08.036, (File:ERMES.png|thumb|alt=ERMES tethering complex.|Model of the yeast multimeric tethering complex, ERMES)


The MAM is a critical signaling, metabolic, and trafficking hub in the cell that allows for the integration of ER and mitochondrial physiology. Coupling between these organelles is not simply structural but functional as well and critical for overall cellular physiology and homeostasis. The MAM thus offers a perspective on mitochondria that diverges from the traditional view of this organelle as a static, isolated unit appropriated for its metabolic capacity by the cell. Instead, this mitochondrial-ER interface emphasizes the integration of the mitochondria, the product of an endosymbiotic event, into diverse cellular processes.

Organization and distribution

File:HeLa mtGFP.tif|thumb|Typical mitochondrial network (green) in two human cells (HeLa cellsHeLa cellsMitochondria (and related structures) are found in all eukaryotes (except one—the Oxymonad Monocercomonoides sp.).JOURNAL, Karnkowska A, Vacek V, Zubáčová Z, Treitli SC, Petrželková R, Eme L, Novák L, Žárský V, Barlow LD, Herman EK, Soukal P, Hroudová M, Doležal P, Stairs CW, Roger AJ, Eliáš M, Dacks JB, Vlček Č, Hampl V, A Eukaryote without a Mitochondrial Organelle, Current Biology, 26, 10, 1274–1284, May 2016, 27185558, 10.1016/j.cub.2016.03.053, The eukaryote Giardia lamblia, for example, does not contain mitochondria, but does have a mitochondrial-like gene, suggesting that it once included either mitochondria or an endosymbiotic progenitor of it JOURNAL, Roger AJ, Svärd SG, Tovar J, Clark CG, Smith MW, Gillin FD, Sogin ML, A mitochondrial-like chaperonin 60 gene in Giardia lamblia: evidence that diplomonads once harbored an endosymbiont related to the progenitor of mitochondria, Proceedings of the National Academy of Sciences of the United States of America, 95, 1, 229–234, January 1998, 9419358, 18184, 10.1073/pnas.95.1.229, yes, 1998PNAS...95..229R, Although commonly depicted as bean-like structures they form a highly dynamic network in the majority of cells where they constantly undergo fission and fusion. The population of all the mitochondria of a given cell constitutes the chondriome.JOURNAL, Logan DC, Mitochondrial fusion, division and positioning in plants, Biochemical Society Transactions, 38, 3, 789–95, June 2010, 20491666, 10.1042/bst0380789, Mitochondria vary in number and location according to cell type. A single mitochondrion is often found in unicellular organisms. Conversely, the chondriome size of human liver cells is large, with about 1000–2000 mitochondria per cell, making up 1/5 of the cell volume. The mitochondrial content of otherwise similar cells can vary substantially in size and membrane potential,JOURNAL, das Neves RP, Jones NS, Andreu L, Gupta R, Enver T, Iborra FJ, Connecting variability in global transcription rate to mitochondrial variability, PLoS Biology, 8, 12, e1000560, December 2010, 21179497, 3001896, 10.1371/journal.pbio.1000560, Weissman, Jonathan S, with differences arising from sources including uneven partitioning at cell divisions, leading to extrinsic differences in ATP levels and downstream cellular processes.JOURNAL, Johnston IG, Gaal B, Neves RP, Enver T, Iborra FJ, Jones NS, Mitochondrial variability as a source of extrinsic cellular noise, PLoS Computational Biology, 8, 3, e1002416, 2012, 22412363, 3297557, 10.1371/journal.pcbi.1002416, Haugh, Jason M, 1107.4499, 2012PLSCB...8E2416J, The mitochondria can be found nestled between myofibrils of muscle or wrapped around the sperm flagellum. Often, they form a complex 3D branching network inside the cell with the cytoskeleton. The association with the cytoskeleton determines mitochondrial shape, which can affect the function as well:JOURNAL, Rappaport L, Oliviero P, Samuel JL, Cytoskeleton and mitochondrial morphology and function, Mol. Cell. Biochem., 184, 101–105, 1998, 10.1023/A:1006843113166, different structures of the mitochondrial network may afford the population a variety of physical, chemical, and signalling advantages or disadvantages.JOURNAL, Hoitzing H, Johnston IG, Jones NS, What is the function of mitochondrial networks? A theoretical assessment of hypotheses and proposal for future research, BioEssays, 37, 6, 687–700, June 2015, 25847815, 4672710, 10.1002/bies.201400188, Mitochondria in cells are always distributed along microtubules and the distribution of these organelles is also correlated with the endoplasmic reticulum.JOURNAL, Soltys BJ, Gupta RS, Interrelationships of endoplasmic reticulum, mitochondria, intermediate filaments, and microtubules--a quadruple fluorescence labeling study, Biochemistry and Cell Biology, 70, 10–11, 1174–1186, 1992, 1363623, 10.1139/o92-163, Recent evidence suggests that vimentin, one of the components of the cytoskeleton, is also critical to the association with the cytoskeleton.JOURNAL, Tang HL, Lung HL, Wu KC, Le AH, Tang HM, Fung MC, Vimentin supports mitochondrial morphology and organization, The Biochemical Journal, 410, 1, 141–146, February 2008, 17983357, 10.1042/BJ20071072,


The most prominent roles of mitochondria are to produce the energy currency of the cell, ATP (i.e., phosphorylation of ADP), through respiration, and to regulate cellular metabolism. The central set of reactions involved in ATP production are collectively known as the citric acid cycle, or the Krebs cycle. However, the mitochondrion has many other functions in addition to the production of ATP.

Energy conversion

A dominant role for the mitochondria is the production of ATP, as reflected by the large number of proteins in the inner membrane for this task. This is done by oxidizing the major products of glucose: pyruvate, and NADH, which are produced in the cytosol. This type of cellular respiration known as aerobic respiration, is dependent on the presence of oxygen. When oxygen is limited, the glycolytic products will be metabolized by anaerobic fermentation, a process that is independent of the mitochondria. The production of ATP from glucose has an approximately 13-times higher yield during aerobic respiration compared to fermentation.JOURNAL, Rich PR, The molecular machinery of Keilin's respiratory chain, Biochemical Society Transactions, 31, Pt 6, 1095–1105, December 2003, 14641005, 10.1042/BST0311095, Plant mitochondria can also produce a limited amount of ATP without oxygen by using the alternate substrate nitrite.JOURNAL, Stoimenova M, Igamberdiev AU, Gupta KJ, Hill RD, Nitrite-driven anaerobic ATP synthesis in barley and rice root mitochondria, Planta, 226, 2, 465–474, July 2007, 17333252, 10.1007/s00425-007-0496-0, ATP crosses out through the inner membrane with the help of a specific protein, and across the outer membrane via porins. ADP returns via the same route.

Pyruvate and the citric acid cycle

Pyruvate molecules produced by glycolysis are actively transported across the inner mitochondrial membrane, and into the matrix where they can either be oxidized and combined with coenzyme A to form CO2, acetyl-CoA, and NADH, or they can be carboxylated (by pyruvate carboxylase) to form oxaloacetate. This latter reaction ”fills up” the amount of oxaloacetate in the citric acid cycle, and is therefore an anaplerotic reaction, increasing the cycle’s capacity to metabolize acetyl-CoA when the tissue's energy needs (e.g. in muscle) are suddenly increased by activity.BOOK, Stryer, Lubert, vanc, In: Biochemistry., Citric acid cycle., Fourth, New York, W.H. Freeman and Company, 1995, 509–527, 569–579, 614–616, 638–641, 732–735, 739–748, 770–773, 0-7167-2009-4, In the citric acid cycle, all the intermediates (e.g. citrate, iso-citrate, alpha-ketoglutarate, succinate, fumarate, malate and oxaloacetate) are regenerated during each turn of the cycle. Adding more of any of these intermediates to the mitochondrion therefore means that the additional amount is retained within the cycle, increasing all the other intermediates as one is converted into the other. Hence, the addition of any one of them to the cycle has an anaplerotic effect, and its removal has a cataplerotic effect. These anaplerotic and cataplerotic reactions will, during the course of the cycle, increase or decrease the amount of oxaloacetate available to combine with acetyl-CoA to form citric acid. This in turn increases or decreases the rate of ATP production by the mitochondrion, and thus the availability of ATP to the cell.Acetyl-CoA, on the other hand, derived from pyruvate oxidation, or from the beta-oxidation of fatty acids, is the only fuel to enter the citric acid cycle. With each turn of the cycle one molecule of acetyl-CoA is consumed for every molecule of oxaloacetate present in the mitochondrial matrix, and is never regenerated. It is the oxidation of the acetate portion of acetyl-CoA that produces CO2 and water, with the energy thus released captured in the form of ATP.In the liver, the carboxylation of cytosolic pyruvate into intra-mitochondrial oxaloacetate is an early step in the gluconeogenic pathway, which converts lactate and de-aminated alanine into glucose, under the influence of high levels of glucagon and/or epinephrine in the blood. Here, the addition of oxaloacetate to the mitochondrion does not have a net anaplerotic effect, as another citric acid cycle intermediate (malate) is immediately removed from the mitochondrion to be converted into cytosolic oxaloacetate, which is ultimately converted into glucose, in a process that is almost the reverse of glycolysis.The enzymes of the citric acid cycle are located in the mitochondrial matrix, with the exception of succinate dehydrogenase, which is bound to the inner mitochondrial membrane as part of Complex II.JOURNAL, King A, Selak MA, Gottlieb E, Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer, Oncogene, 25, 34, 4675–4682, August 2006, 16892081, 10.1038/sj.onc.1209594, The citric acid cycle oxidizes the acetyl-CoA to carbon dioxide, and, in the process, produces reduced cofactors (three molecules of NADH and one molecule of FADH2) that are a source of electrons for the electron transport chain, and a molecule of GTP (that is readily converted to an ATP).

NADH and FADH2: the electron transport chain

(File:Electron transport chain.svg|thumb|400px|Electron transport chain in the mitochondrial intermembrane space)The redox energy from NADH and FADH2 is transferred to oxygen (O2) in several steps via the electron transport chain. These energy-rich molecules are produced within the matrix via the citric acid cycle but are also produced in the cytoplasm by glycolysis. Reducing equivalents from the cytoplasm can be imported via the malate-aspartate shuttle system of antiporter proteins or feed into the electron transport chain using a glycerol phosphate shuttle. Protein complexes in the inner membrane (NADH dehydrogenase (ubiquinone), cytochrome c reductase, and cytochrome c oxidase) perform the transfer and the incremental release of energy is used to pump protons (H+) into the intermembrane space. This process is efficient, but a small percentage of electrons may prematurely reduce oxygen, forming reactive oxygen species such as superoxide. This can cause oxidative stress in the mitochondria and may contribute to the decline in mitochondrial function associated with the aging process.JOURNAL, Huang H, Manton KG, The role of oxidative damage in mitochondria during aging: a review, Frontiers in Bioscience, 9, 1–3, 1100–1117, May 2004, 14977532, 10.2741/1298, As the proton concentration increases in the intermembrane space, a strong electrochemical gradient is established across the inner membrane. The protons can return to the matrix through the ATP synthase complex, and their potential energy is used to synthesize ATP from ADP and inorganic phosphate (Pi). This process is called chemiosmosis, and was first described by Peter MitchellJOURNAL, Mitchell P, Moyle J, Chemiosmotic hypothesis of oxidative phosphorylation, Nature, 213, 5072, 137–139, January 1967, 4291593, 10.1038/213137a0, 1967Natur.213..137M, JOURNAL, Mitchell P, Proton current flow in mitochondrial systems, Nature, 214, 5095, 1327–1328, June 1967, 6056845, 10.1038/2141327a0, 1967Natur.214.1327M, who was awarded the 1978 Nobel Prize in Chemistry for his work. Later, part of the 1997 Nobel Prize in Chemistry was awarded to Paul D. Boyer and John E. Walker for their clarification of the working mechanism of ATP synthase.WEB, Nobel Foundation, Chemistry 1997,weblink 2007-12-16,

Heat production

Under certain conditions, protons can re-enter the mitochondrial matrix without contributing to ATP synthesis. This process is known as proton leak or mitochondrial uncoupling and is due to the facilitated diffusion of protons into the matrix. The process results in the unharnessed potential energy of the proton electrochemical gradient being released as heat. The process is mediated by a proton channel called thermogenin, or UCP1.JOURNAL, Mozo J, Emre Y, Bouillaud F, Ricquier D, Criscuolo F, Thermoregulation: what role for UCPs in mammals and birds?, Bioscience Reports, 25, 3–4, 227–249, November 2005, 16283555, 10.1007/s10540-005-2887-4, Thermogenin is a 33 kDa protein first discovered in 1973.JOURNAL, Nicholls DG, Lindberg O, Brown-adipose-tissue mitochondria. The influence of albumin and nucleotides on passive ion permeabilities, European Journal of Biochemistry, 37, 3, 523–530, September 1973, 4777251, 10.1111/j.1432-1033.1973.tb03014.x, Thermogenin is primarily found in brown adipose tissue, or brown fat, and is responsible for non-shivering thermogenesis. Brown adipose tissue is found in mammals, and is at its highest levels in early life and in hibernating animals. In humans, brown adipose tissue is present at birth and decreases with age.

Storage of calcium ions

File:Chondrocyte- calcium stain.jpg|right|thumb|400 px|Transmission electron micrograph of a chondrocytechondrocyteThe concentrations of free calcium in the cell can regulate an array of reactions and is important for signal transduction in the cell. Mitochondria can transiently store calcium, a contributing process for the cell's homeostasis of calcium.JOURNAL, Santulli G, Xie W, Reiken SR, Marks AR, Mitochondrial calcium overload is a key determinant in heart failure, Proceedings of the National Academy of Sciences of the United States of America, 112, 36, 11389–11394, September 2015, 26217001, 4568687, 10.1073/pnas.1513047112, 2015PNAS..11211389S, BOOK, Siegel GJ, Agranoff BW, Fisher SK, Albers RW, Uhler MD, Basic Neurochemistry, 6, 1999, 978-0-397-51820-3, Lippincott Williams & Wilkins, . Illustrations by Lorie M. Gavulic, In fact, their ability to rapidly take in calcium for later release makes them very good "cytosolic buffers" for calcium.JOURNAL, Brighton CT, Hunt RM, Mitochondrial calcium and its role in calcification. Histochemical localization of calcium in electron micrographs of the epiphyseal growth plate with K-pyroantimonate, Clinical Orthopaedics and Related Research, 100, 5, 406–416, May 1974, 4134194, 10.1097/00003086-197405000-00057, JOURNAL, Brighton CT, Hunt RM, The role of mitochondria in growth plate calcification as demonstrated in a rachitic model, The Journal of Bone and Joint Surgery. American Volume, 60, 5, 630–639, July 1978, 681381, 10.2106/00004623-197860050-00007, The endoplasmic reticulum (ER) is the most significant storage site of calcium, and there is a significant interplay between the mitochondrion and ER with regard to calcium.JOURNAL, Pizzo P, Pozzan T, Mitochondria-endoplasmic reticulum choreography: structure and signaling dynamics, Trends in Cell Biology, 17, 10, 511–517, October 2007, 17851078, 10.1016/j.tcb.2007.07.011, The calcium is taken up into the matrix by the mitochondrial calcium uniporter on the inner mitochondrial membrane.JOURNAL, Miller RJ, Mitochondria – the kraken wakes!, Trends Neurosci., 21, 3, March 1, 1998, 95–97, 10.1016/S0166-2236(97)01206-X, It is primarily driven by the mitochondrial membrane potential. Release of this calcium back into the cell's interior can occur via a sodium-calcium exchange protein or via "calcium-induced-calcium-release" pathways. This can initiate calcium spikes or calcium waves with large changes in the membrane potential. These can activate a series of second messenger system proteins that can coordinate processes such as neurotransmitter release in nerve cells and release of hormones in endocrine cells.JOURNAL, Santulli G, Pagano G, Sardu C, Xie W, Reiken S, D'Ascia SL, Cannone M, Marziliano N, Trimarco B, Guise TA, Lacampagne A, Marks AR, Calcium release channel RyR2 regulates insulin release and glucose homeostasis, The Journal of Clinical Investigation, 125, 5, 1968–1978, May 2015, 25844899, 4463204, 10.1172/JCI79273, Ca2+ influx to the mitochondrial matrix has recently been implicated as a mechanism to regulate respiratory bioenergetics by allowing the electrochemical potential across the membrane to transiently "pulse" from ΔΨ-dominated to pH-dominated, facilitating a reduction of oxidative stress.JOURNAL, Schwarzländer M, Logan DC, Johnston IG, Jones NS, Meyer AJ, Fricker MD, Sweetlove LJ, Pulsing of membrane potential in individual mitochondria: a stress-induced mechanism to regulate respiratory bioenergetics in Arabidopsis, The Plant Cell, 24, 3, 1188–1201, March 2012, 22395486, 3336130, 10.1105/tpc.112.096438, In neurons, concomitant increases in cytosolic and mitochondrial calcium act to synchronize neuronal activity with mitochondrial energy metabolism. Mitochondrial matrix calcium levels can reach the tens of micromolar levels, which is necessary for the activation of isocitrate dehydrogenase, one of the key regulatory enzymes of the Krebs cycle.JOURNAL, Ivannikov MV, Macleod GT, Mitochondrial free Ca²⁺ levels and their effects on energy metabolism in Drosophila motor nerve terminals, Biophysical Journal, 104, 11, 2353–2361, June 2013, 23746507, 3672877, 10.1016/j.bpj.2013.03.064, 2013BpJ...104.2353I,

Additional functions

Mitochondria play a central role in many other metabolic tasks, such as:
  • Signaling through mitochondrial reactive oxygen speciesJOURNAL, Li X, Fang P, Mai J, Choi ET, Wang H, Yang XF, Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers, Journal of Hematology & Oncology, 6, 19, 19, February 2013, 23442817, 3599349, 10.1186/1756-8722-6-19,
  • Regulation of the membrane potential
  • Apoptosis-programmed cell deathJOURNAL, Green DR, Apoptotic pathways: the roads to ruin, Cell, 94, 6, 695–698, September 1998, 9753316, 10.1016/S0092-8674(00)81728-6,
  • Calcium signaling (including calcium-evoked apoptosis)JOURNAL, Hajnóczky G, Csordás G, Das S, Garcia-Perez C, Saotome M, Sinha Roy S, Yi M, Mitochondrial calcium signalling and cell death: approaches for assessing the role of mitochondrial Ca2+ uptake in apoptosis, Cell Calcium, 40, 5–6, 553–560, 2006, 17074387, 2692319, 10.1016/j.ceca.2006.08.016,
  • Regulation of cellular metabolismJOURNAL, McBride HM, Neuspiel M, Wasiak S, Mitochondria: more than just a powerhouse, Current Biology, 16, 14, R551–60, July 2006, 16860735, 10.1016/j.cub.2006.06.054,
  • Certain heme synthesis reactionsJOURNAL, Oh-hama T, Evolutionary consideration on 5-aminolevulinate synthase in nature, Origins of Life and Evolution of the Biosphere, 27, 4, 405–412, August 1997, 9249985, 10.1023/A:1006583601341, (see also: porphyrin)
  • Steroid synthesis.JOURNAL, Rossier MF, T channels and steroid biosynthesis: in search of a link with mitochondria, Cell Calcium, 40, 2, 155–164, August 2006, 16759697, 10.1016/j.ceca.2006.04.020,
  • Hormonal signaling JOURNAL, Klinge CM, Estrogenic control of mitochondrial function and biogenesis, Journal of Cellular Biochemistry, 105, 6, 1342–1351, December 2008, 18846505, 2593138, 10.1002/jcb.21936, Mitochondria are sensitive and responsive to hormones, in part by the action of mitochondrial estrogen receptors (mtERs). These receptors have been found in various tissues and cell types, including brain JOURNAL, Alvarez-Delgado C, Mendoza-Rodríguez CA, Picazo O, Cerbón M, Different expression of alpha and beta mitochondrial estrogen receptors in the aging rat brain: interaction with respiratory complex V, Experimental Gerontology, 45, 7–8, 580–585, August 2010, 20096765, 10.1016/j.exger.2010.01.015, and heart JOURNAL, Pavón N, Martínez-Abundis E, Hernández L, Gallardo-Pérez JC, Alvarez-Delgado C, Cerbón M, Pérez-Torres I, Aranda A, Chávez E, Sexual hormones: effects on cardiac and mitochondrial activity after ischemia-reperfusion in adult rats. Gender difference, The Journal of Steroid Biochemistry and Molecular Biology, 132, 1–2, 135–146, October 2012, 22609314, 10.1016/j.jsbmb.2012.05.003,
Some mitochondrial functions are performed only in specific types of cells. For example, mitochondria in liver cells contain enzymes that allow them to detoxify ammonia, a waste product of protein metabolism. A mutation in the genes regulating any of these functions can result in mitochondrial diseases.

Cellular proliferation regulation

The relationship between cellular proliferation and mitochondria has been investigated using cervical cancer HeLa cells. Tumor cells require an ample amount of ATP (Adenosine triphosphate) in order to synthesize bioactive compounds such as lipids, proteins, and nucleotides for rapid cell proliferation.JOURNAL, Weinberg F, Chandel NS, Mitochondrial metabolism and cancer, Annals of the New York Academy of Sciences, 1177, 1, 66–73, October 2009, 19845608, 10.1111/j.1749-6632.2009.05039.x, 2009NYASA1177...66W, The majority of ATP in tumor cells is generated via the oxidative phosphorylation pathway (OxPhos).JOURNAL, Moreno-Sánchez R, Rodríguez-Enríquez S, Marín-Hernández A, Saavedra E, Energy metabolism in tumor cells, The FEBS Journal, 274, 6, 1393–1418, March 2007, 17302740, 10.1111/j.1742-4658.2007.05686.x, Interference with OxPhos have shown to cause cell cycle arrest suggesting that mitochondria play a role in cell proliferation. Mitochondrial ATP production is also vital for cell division in addition to other basic functions in the cell including the regulation of cell volume, solute concentration, and cellular architecture.JOURNAL, Pedersen PL, ATP synthase. The machine that makes ATP, Current Biology, 4, 12, 1138–1141, December 1994, 7704582, 10.1016/S0960-9822(00)00257-8, JOURNAL, Pattappa G, Heywood HK, de Bruijn JD, Lee DA, The metabolism of human mesenchymal stem cells during proliferation and differentiation, Journal of Cellular Physiology, 226, 10, 2562–2570, October 2011, 21792913, 10.1002/jcp.22605, JOURNAL, Agarwal B, A role for anions in ATP synthesis and its molecular mechanistic interpretation, Journal of Bioenergetics and Biomembranes, 43, 3, 299–310, June 2011, 21647635, 10.1007/s10863-011-9358-3, ATP levels differ at various stages of the cell cycle suggesting that there is a relationship between the abundance of ATP and the cell's ability to enter a new cell cycle.JOURNAL, Sweet S, Singh G, Changes in mitochondrial mass, membrane potential, and cellular adenosine triphosphate content during the cell cycle of human leukemic (HL-60) cells, Journal of Cellular Physiology, 180, 1, 91–96, July 1999, 10362021, 10.1002/(SICI)1097-4652(199907)180:13.0.CO;2-6, ATP's role in the basic functions of the cell make the cell cycle sensitive to changes in the availability of mitochondrial derived ATP. The variation in ATP levels at different stages of the cell cycle support the hypothesis that mitochondria play an important role in cell cycle regulation. Although the specific mechanisms between mitochondria and the cell cycle regulation is not well understood, studies have shown that low energy cell cycle checkpoints monitor the energy capability before committing to another round of cell division.


File:Map of the human mitochondrial genome.svg|thumb|right|300px|The circular 16,569 bp human mitochondrial genome encoding 37 genes, i.e., 28 on the H-strand and 9 on the L-strand.]]Mitochondria contain their own genome, an indication that they are derived from bacteria through endosymbiosis. However, the ancestral endosymbiont genome has lost most of its genes so that the mitochondrial genome (mitogenome) is one of the most reduced genomes across organisms.The human mitochondrial genome is a circular DNA molecule of about 16 kilobases.JOURNAL, Chan DC, Mitochondria: dynamic organelles in disease, aging, and development, Cell, 125, 7, 1241–1252, June 2006, 16814712, 10.1016/j.cell.2006.06.010, It encodes 37 genes: 13 for subunits of respiratory complexes I, III, IV and V, 22 for mitochondrial tRNA (for the 20 standard amino acids, plus an extra gene for leucine and serine), and 2 for rRNA. One mitochondrion can contain two to ten copies of its DNA.JOURNAL, Wiesner RJ, Rüegg JC, Morano I, Counting target molecules by exponential polymerase chain reaction: copy number of mitochondrial DNA in rat tissues, Biochemical and Biophysical Research Communications, 183, 2, 553–559, March 1992, 1550563, 10.1016/0006-291X(92)90517-O, As in prokaryotes, there is a very high proportion of coding DNA and an absence of repeats. Mitochondrial genes are transcribed as multigenic transcripts, which are cleaved and polyadenylated to yield mature mRNAs. Not all proteins necessary for mitochondrial function are encoded by the mitochondrial genome; most are coded by genes in the cell nucleus and the corresponding proteins are imported into the mitochondrion.JOURNAL, Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, Schreier PH, Smith AJ, Staden R, Young IG, Sequence and organization of the human mitochondrial genome, Nature, 290, 5806, 457–465, April 1981, 7219534, 10.1038/290457a0, 1981Natur.290..457A, The exact number of genes encoded by the nucleus and the mitochondrial genome differs between species. Most mitochondrial genomes are circular, although exceptions have been reported.JOURNAL, Fukuhara H, Sor F, Drissi R, Dinouël N, Miyakawa I, Rousset S, Viola AM, Linear mitochondrial DNAs of yeasts: frequency of occurrence and general features, Molecular and Cellular Biology, 13, 4, 2309–2314, April 1993, 8455612, 359551, 10.1128/mcb.13.4.2309, In general, mitochondrial DNA lacks introns, as is the case in the human mitochondrial genome; however, introns have been observed in some eukaryotic mitochondrial DNA,JOURNAL, Bernardi G, Intervening sequences in the mitochondrial genome, Nature, 276, 5688, 558–559, December 1978, 214710, 10.1038/276558a0, 1978Natur.276..558B, such as that of yeastJOURNAL, Hebbar SK, Belcher SM, Perlman PS, A maturase-encoding group IIA intron of yeast mitochondria self-splices in vitro, Nucleic Acids Research, 20, 7, 1747–1754, April 1992, 1579468, 312266, 10.1093/nar/20.7.1747, and protists,JOURNAL, Gray MW, Lang BF, Cedergren R, Golding GB, Lemieux C, Sankoff D, Turmel M, Brossard N, Delage E, Littlejohn TG, Plante I, Rioux P, Saint-Louis D, Zhu Y, Burger G, Genome structure and gene content in protist mitochondrial DNAs, Nucleic Acids Research, 26, 4, 865–878, February 1998, 9461442, 147373, 10.1093/nar/26.4.865, including Dictyostelium discoideum.JOURNAL, Gray MW, Lang BF, Burger G, Mitochondria of protists, Annual Review of Genetics, 38, 477–524, 2004, 15568984, 10.1146/annurev.genet.37.110801.142526, Between protein-coding regions, tRNAs are present. During transcription, the tRNAs acquire their characteristic L-shape that gets recognized and cleaved by specific enzymes. Mitochondrial tRNA genes have different sequences from the nuclear tRNAs but lookalikes of mitochondrial tRNAs have been found in the nuclear chromosomes with high sequence similarity.JOURNAL, Telonis AG, Loher P, Kirino Y, Rigoutsos I, Nuclear and mitochondrial tRNA-lookalikes in the human genome, Frontiers in Genetics, 5, 344, 2014, 25339973, 4189335, 10.3389/fgene.2014.00344, In animals, the mitochondrial genome is typically a single circular chromosome that is approximately 16 kb long and has 37 genes. The genes, while highly conserved, may vary in location. Curiously, this pattern is not found in the human body louse (Pediculus humanus). Instead, this mitochondrial genome is arranged in 18 minicircular chromosomes, each of which is 3–4 kb long and has one to three genes.JOURNAL, Shao R, Kirkness EF, Barker SC, The single mitochondrial chromosome typical of animals has evolved into 18 minichromosomes in the human body louse, Pediculus humanus, Genome Research, 19, 5, 904–912, May 2009, 19336451, 2675979, 10.1101/gr.083188.108, This pattern is also found in other sucking lice, but not in chewing lice. Recombination has been shown to occur between the minichromosomes. The reason for this difference is not known.

Alternative genetic code

While slight variations on the standard genetic code had been predicted earlier,JOURNAL, Crick FH, Orgel LE, yes, 10.1016/0019-1035(73)90110-3,weblink 1973, Directed panspermia, Icarus, 19, 3, 341–346, p. 344: It is a little surprising that organisms with somewhat different codes do not coexist., 1973Icar...19..341C, Further discussion. none was discovered until 1979, when researchers studying human mitochondrial genes determined that they used an alternative code.JOURNAL, Barrell BG, Bankier AT, Drouin J, A different genetic code in human mitochondria, Nature, 282, 5735, 189–194, November 1979, 226894, 10.1038/282189a0, 1979Natur.282..189B, However, the mitochondria of many other eukaryotes, including most plants, use the standard code.Mitochondrial Genetic Code in Taxonomy Tree. NCBI Many slight variants have been discovered since,Elzanowski, Andrzej and Ostell, Jim. The Genetic Codes. NCBI including various alternative mitochondrial codes.JOURNAL, Jukes TH, Osawa S, The genetic code in mitochondria and chloroplasts, Experientia, 46, 11–12, 1117–1126, December 1990, 2253709, 10.1007/BF01936921, Further, the AUA, AUC, and AUU codons are all allowable start codons.{|class="wikitable"|+Exceptions to the standard genetic code in mitochondria!Organism!!Codon!!Standard!!Mitochondria
|Mammals|AGA, AGG|Arginine|Stop codon
|Invertebrates|AGA, AGG|Arginine|Serine
All of the above|AUA|Isoleucine|Methionine
|UGA|Stop codon|Tryptophan
Some of these differences should be regarded as pseudo-changes in the genetic code due to the phenomenon of RNA editing, which is common in mitochondria. In higher plants, it was thought that CGG encoded for tryptophan and not arginine; however, the codon in the processed RNA was discovered to be the UGG codon, consistent with the standard genetic code for tryptophan.JOURNAL, Hiesel R, Wissinger B, Schuster W, Brennicke A, RNA editing in plant mitochondria, Science, 246, 4937, 1632–1634, December 1989, 2480644, 10.1126/science.2480644, 1989Sci...246.1632H, Of note, the arthropod mitochondrial genetic code has undergone parallel evolution within a phylum, with some organisms uniquely translating AGG to lysine.JOURNAL, Abascal F, Posada D, Knight RD, Zardoya R, Parallel evolution of the genetic code in arthropod mitochondrial genomes, PLoS Biology, 4, 5, e127, May 2006, 16620150, 1440934, 10.1371/journal.pbio.0040127,

Evolution and diversity

Mitochondrial genomes have far fewer genes than the bacteria from which they are thought to be descended. Although some have been lost altogether, many have been transferred to the nucleus, such as the respiratory complex II protein subunits. This is thought to be relatively common over evolutionary time. A few organisms, such as the Cryptosporidium, actually have mitochondria that lack any DNA, presumably because all their genes have been lost or transferred.JOURNAL, Henriquez FL, Richards TA, Roberts F, McLeod R, Roberts CW, The unusual mitochondrial compartment of Cryptosporidium parvum, Trends in Parasitology, 21, 2, 68–74, February 2005, 15664529, 10.1016/, In Cryptosporidium, the mitochondria have an altered ATP generation system that renders the parasite resistant to many classical mitochondrial inhibitors such as cyanide, azide, and atovaquone.

Replication and inheritance

Mitochondria divide by binary fission, similar to bacterial cell division.BOOK, Pfeiffer, Ronald F., vanc, Parkinson's Disease, 2012, CRC Press, 583,weblink 9781439807149, The regulation of this division differs between eukaryotes. In many single-celled eukaryotes, their growth and division is linked to the cell cycle. For example, a single mitochondrion may divide synchronously with the nucleus. This division and segregation process must be tightly controlled so that each daughter cell receives at least one mitochondrion. In other eukaryotes (in mammals for example), mitochondria may replicate their DNA and divide mainly in response to the energy needs of the cell, rather than in phase with the cell cycle. When the energy needs of a cell are high, mitochondria grow and divide. When the energy use is low, mitochondria are destroyed or become inactive. In such examples, and in contrast to the situation in many single celled eukaryotes, mitochondria are apparently randomly distributed to the daughter cells during the division of the cytoplasm. Understanding of mitochondrial dynamics, which is described as the balance between mitochondrial fusion and fission, has revealed that functional and structural alterations in mitochondrial morphology are important factors in pathologies associated with several disease conditions.JOURNAL, Seo AY, Joseph AM, Dutta D, Hwang JC, Aris JP, Leeuwenburgh C, New insights into the role of mitochondria in aging: mitochondrial dynamics and more, Journal of Cell Science, 123, Pt 15, 2533–2542, August 2010, 20940129, 2912461, 10.1242/jcs.070490, The hypothesis of mitochondrial binary fission has relied on the visualization by fluorescence microscopy and conventional transmission electron microscopy (TEM). The resolution of fluorescence microscopy(~200 nm) is insufficient to distinguish structural details, such as double mitochondrial membrane in mitochondrial division or even to distinguish individual mitochondria when several are close together. Conventional TEM has also some technical limitations{{which|date=January 2016}} in verifying mitochondrial division. Cryo-electron tomography was recently used to visualize mitochondrial division in frozen hydrated intact cells. It revealed that mitochondria divide by budding.JOURNAL, Hu GB, Whole cell cryo-electron tomography suggests mitochondria divide by budding, Microscopy and Microanalysis, 20, 4, 1180–1187, August 2014, 24870811, 10.1017/S1431927614001317, 2014MiMic..20.1180H, An individual's mitochondrial genes are not inherited by the same mechanism as nuclear genes. Typically, the mitochondria are inherited from one parent only. In humans, when an egg cell is fertilized by a sperm, the egg nucleus and sperm nucleus each contribute equally to the genetic makeup of the zygote nucleus. In contrast, the mitochondria, and therefore the mitochondrial DNA, usually come from the egg only. The sperm's mitochondria enter the egg, but do not contribute genetic information to the embryo.Kimball, J.W. (2006) "Sexual Reproduction in Humans: Copulation and Fertilization," Kimball's Biology Pages (based on Biology, 6th ed., 1996) Instead, paternal mitochondria are marked with ubiquitin to select them for later destruction inside the embryo.JOURNAL, Sutovsky P, Moreno RD, Ramalho-Santos J, Dominko T, Simerly C, Schatten G, Ubiquitin tag for sperm mitochondria, Nature, 402, 6760, 371–372, November 1999, 10586873, 10.1038/46466, 1999Natur.402..371S, Discussed in Science News. The egg cell contains relatively few mitochondria, but it is these mitochondria that survive and divide to populate the cells of the adult organism. Mitochondria are, therefore, in most cases inherited only from mothers, a pattern known as maternal inheritance. This mode is seen in most organisms, including the majority of animals. However, mitochondria in some species can sometimes be inherited paternally. This is the norm among certain coniferous plants, although not in pine trees and yews.JOURNAL, Mogensen HL, 1996, The Hows and Whys of Cytoplasmic Inheritance in Seed Plants, American Journal of Botany, 83, 383–404, 10.2307/2446172, 3, 2446172, For Mytilids, paternal inheritance only occurs within males of the species.JOURNAL, Zouros E, The exceptional mitochondrial DNA system of the mussel family Mytilidae, Genes & Genetic Systems, 75, 6, 313–318, December 2000, 11280005, 10.1266/ggs.75.313, JOURNAL, Sutherland B, Stewart D, Kenchington ER, Zouros E, The fate of paternal mitochondrial DNA in developing female mussels, Mytilus edulis: implications for the mechanism of doubly uniparental inheritance of mitochondrial DNA, Genetics, 148, 1, 341–347, January 1998, 9475744, 1459795, Male and Female Mitochondrial DNA Lineages in the Blue Mussel (Mytilus edulis) Species Group by Donald T. Stewart, Carlos Saavedra, Rebecca R. Stanwood, Amy 0. Ball, and Eleftherios Zouros It has been suggested that it occurs at a very low level in humans.JOURNAL, Johns DR, Paternal transmission of mitochondrial DNA is (fortunately) rare, Annals of Neurology, 54, 4, 422–424, October 2003, 14520651, 10.1002/ana.10771, There is a recent suggestion that mitochondria that shorten male lifespan stay in the system because they are inherited only through the mother. By contrast, natural selection weeds out mitochondria that reduce female survival as such mitochondria are less likely to be passed on to the next generation. Therefore, it is suggested that human females and female animals tend to live longer than males. The authors claim that this is a partial explanation.Fruit flies offer DNA clue to why women live longer. BBC. 2 August 2012Uniparental inheritance leads to little opportunity for genetic recombination between different lineages of mitochondria, although a single mitochondrion can contain 2–10 copies of its DNA. For this reason, mitochondrial DNA is usually thought to reproduce by binary fission. What recombination does take place maintains genetic integrity rather than maintaining diversity. However, there are studies showing evidence of recombination in mitochondrial DNA. It is clear that the enzymes necessary for recombination are present in mammalian cells.JOURNAL, Thyagarajan B, Padua RA, Campbell C, Mammalian mitochondria possess homologous DNA recombination activity, The Journal of Biological Chemistry, 271, 44, 27536–27543, November 1996, 8910339, 10.1074/jbc.271.44.27536, Further, evidence suggests that animal mitochondria can undergo recombination.JOURNAL, Lunt DH, Hyman BC, Animal mitochondrial DNA recombination, Nature, 387, 6630, 247, May 1997, 9153388, 10.1038/387247a0, 1997Natur.387..247L, The data are a bit more controversial in humans, although indirect evidence of recombination exists.JOURNAL, Eyre-Walker A, Smith NH, Smith JM, How clonal are human mitochondria?, Proceedings. Biological Sciences, 266, 1418, 477–483, March 1999, 10189711, 1689787, 10.1098/rspb.1999.0662, JOURNAL, Awadalla P, Eyre-Walker A, Smith JM, Linkage disequilibrium and recombination in hominid mitochondrial DNA, Science, 286, 5449, 2524–2525, December 1999, 10617471, 10.1126/science.286.5449.2524, If recombination does not occur, the whole mitochondrial DNA sequence represents a single haplotype, which makes it useful for studying the evolutionary history of populations.Entities undergoing uniparental inheritance and with little to no recombination may be expected to be subject to Muller's ratchet, the inexorable accumulation of deleterious mutations until functionality is lost. Animal populations of mitochondria avoid this buildup through a developmental process known as the mtDNA bottleneck. The bottleneck exploits stochastic processes in the cell to increase in the cell-to-cell variability in mutant load as an organism develops: a single egg cell with some proportion of mutant mtDNA thus produces an embryo where different cells have different mutant loads. Cell-level selection may then act to remove those cells with more mutant mtDNA, leading to a stabilisation or reduction in mutant load between generations. The mechanism underlying the bottleneck is debated,JOURNAL, Cree LM, Samuels DC, de Sousa Lopes SC, Rajasimha HK, Wonnapinij P, Mann JR, Dahl HH, Chinnery PF, A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes, Nature Genetics, 40, 2, 249–254, February 2008, 18223651, 10.1038/ng.2007.63, JOURNAL, Cao L, Shitara H, Horii T, Nagao Y, Imai H, Abe K, Hara T, Hayashi J, Yonekawa H, The mitochondrial bottleneck occurs without reduction of mtDNA content in female mouse germ cells, Nature Genetics, 39, 3, 386–390, March 2007, 17293866, 10.1038/ng1970, JOURNAL, Wai T, Teoli D, Shoubridge EA, The mitochondrial DNA genetic bottleneck results from replication of a subpopulation of genomes, Nature Genetics, 40, 12, 1484–1488, December 2008, 19029901, 10.1038/ng.258, with a recent mathematical and experimental metastudy providing evidence for a combination of random partitioning of mtDNAs at cell divisions and random turnover of mtDNA molecules within the cell.JOURNAL, Johnston IG, Burgstaller JP, Havlicek V, Kolbe T, Rülicke T, Brem G, Poulton J, Jones NS, Stochastic modelling, Bayesian inference, and new in vivo measurements elucidate the debated mtDNA bottleneck mechanism, eLife, 4, e07464, June 2015, 26035426, 4486817, 10.7554/eLife.07464,

DNA repair

Mitochondria can repair oxidative DNA damage by mechanisms that are analogous to those occurring in the cell nucleus. The proteins that are employed in mtDNA repair are encoded by nuclear genes, and are translocated to the mitochondria. The DNA repair pathways in mammalian mitochondria include base excision repair, double-strand break repair, direct reversal and mismatch repair.JOURNAL, Gredilla R, Garm C, Stevnsner T, Nuclear and mitochondrial DNA repair in selected eukaryotic aging model systems, Oxid Med Cell Longev, 2012, 282438, 2012, 23050036, 3462412, 10.1155/2012/282438, JOURNAL, Saki M, Prakash A, DNA damage related crosstalk between the nucleus and mitochondria, Free Radic. Biol. Med., 107, 216–227, June 2017, 27915046, 5449269, 10.1016/j.freeradbiomed.2016.11.050, Also DNA damages may be bypassed, rather than repaired, by translesion synthesis.Of the several DNA repair process in mitochondria, the base excision repair pathway is the one that has been most comprehensively studied. Base excision repair is carried out by a sequence of enzymatic catalyzed steps that include recognition and excision of a damaged DNA base, removal of the resulting abasic site, end processing, gap filling and ligation. A common damage in mtDNA that is repaired by base excision repair is 8-oxoguanine produced by the oxidation of guanine.JOURNAL, Leon J, Sakumi K, Castillo E, Sheng Z, Oka S, Nakabeppu Y, 8-Oxoguanine accumulation in mitochondrial DNA causes mitochondrial dysfunction and impairs neuritogenesis in cultured adult mouse cortical neurons under oxidative conditions, Sci Rep, 6, 22086, February 2016, 26912170, 4766534, 10.1038/srep22086, 2016NatSR...622086L, Double-strand breaks can be repaired by homologous recombinational repair in both mammalian mtDNAJOURNAL, Dahal S, Dubey S, Raghavan SC, Homologous recombination-mediated repair of DNA double-strand breaks operates in mammalian mitochondria, Cell. Mol. Life Sci., 75, 9, 1641–1655, May 2018, 29116362, 10.1007/s00018-017-2702-y, and plant mtDNA.JOURNAL, Odahara M, Inouye T, Fujita T, Hasebe M, Sekine Y, Involvement of mitochondrial-targeted RecA in the repair of mitochondrial DNA in the moss, Physcomitrella patens, Genes Genet. Syst., 82, 1, 43–51, February 2007, 17396019, 10.1266/ggs.82.43, Double-strand breaks in mtDNA can also be repaired by microhomology-mediated end joining.JOURNAL, Tadi SK, Sebastian R, Dahal S, Babu RK, Choudhary B, Raghavan SC, Microhomology-mediated end joining is the principal mediator of double-strand break repair during mitochondrial DNA lesions, Mol. Biol. Cell, 27, 2, 223–35, January 2016, 26609070, 4713127, 10.1091/mbc.E15-05-0260, Although there is evidence for the repair processes of direct reversal and mismatch repair in mtDNA, these processes are still not well characterized.

Lack of mitochondrial DNA

Eukaryotic cells typically have mitochondrial DNA; however, mitochondria that lack their own DNA have been found in a marine parasitic dinoflagellate from the genus Amoebophyra. This microorganism, A. cerati, has functional mitochondria that lack a genome.JOURNAL, John U, Lu Y, Wohlrab S, Groth M, Janouškovec J, Kohli GS, Mark FC, Bickmeyer U, Farhat S, Felder M, Frickenhaus S, Guillou L, Keeling PJ, Moustafa A, Porcel BM, Valentin K, Glöckner G, An aerobic eukaryotic parasite with functional mitochondria that likely lacks a mitochondrial genome, Science Advances, 5, 4, eaav1110, April 2019, 31032404, 10.1126/sciadv.aav1110, In related species, the mitochondrial genome still has three genes, but in A. cerati only a single mitochondrial gene — the cytochrome c oxidase I gene (cox1) — is found, and it has migrated to the genome of the nucleus.Veritable powerhouses -- even without DNA: Parasitic algae from the dinoflagellate lineage have organized their genetic material in an unprecedented way - ScienceDaily

Population genetic studies

The near-absence of genetic recombination in mitochondrial DNA makes it a useful source of information for scientists involved in population genetics and evolutionary biology.JOURNAL, Castro JA, Picornell A, Ramon M, Mitochondrial DNA: a tool for populational genetics studies, International Microbiology, 1, 4, 327–332, December 1998, 10943382, Because all the mitochondrial DNA is inherited as a single unit, or haplotype, the relationships between mitochondrial DNA from different individuals can be represented as a gene tree. Patterns in these gene trees can be used to infer the evolutionary history of populations. The classic example of this is in human evolutionary genetics, where the molecular clock can be used to provide a recent date for mitochondrial Eve.JOURNAL, Cann RL, Stoneking M, Wilson AC, Mitochondrial DNA and human evolution, Nature, 325, 6099, 31–36, January 1987, 3025745, 10.1038/325031a0, 1987Natur.325...31C, JOURNAL, Torroni A, Achilli A, Macaulay V, Richards M, Bandelt HJ, Harvesting the fruit of the human mtDNA tree, Trends in Genetics, 22, 6, 339–345, June 2006, 16678300, 10.1016/j.tig.2006.04.001, This is often interpreted as strong support for a recent modern human expansion out of Africa.JOURNAL, Garrigan D, Hammer MF, Reconstructing human origins in the genomic era, Nature Reviews. Genetics, 7, 9, 669–680, September 2006, 16921345, 10.1038/nrg1941, Another human example is the sequencing of mitochondrial DNA from Neanderthal bones. The relatively large evolutionary distance between the mitochondrial DNA sequences of Neanderthals and living humans has been interpreted as evidence for the lack of interbreeding between Neanderthals and anatomically modern humans.JOURNAL, Krings M, Stone A, Schmitz RW, Krainitzki H, Stoneking M, Pääbo S, Neandertal DNA sequences and the origin of modern humans, Cell, 90, 1, 19–30, July 1997, 9230299, 10.1016/S0092-8674(00)80310-4, However, mitochondrial DNA reflects only the history of the females in a population and so may not represent the history of the population as a whole. This can be partially overcome by the use of paternal genetic sequences, such as the non-recombining region of the Y-chromosome. In a broader sense, only studies that also include nuclear DNA can provide a comprehensive evolutionary history of a population.JOURNAL, Harding RM, Fullerton SM, Griffiths RC, Bond J, Cox MJ, Schneider JA, Moulin DS, Clegg JB, Archaic African and Asian lineages in the genetic ancestry of modern humans, American Journal of Human Genetics, 60, 4, 772–789, April 1997, 9106523, 1712470, Recent measurements of the molecular clock for mitochondrial DNAJOURNAL, Soares P, Ermini L, Thomson N, Mormina M, Rito T, Röhl A, Salas A, Oppenheimer S, Macaulay V, Richards MB, Correcting for purifying selection: an improved human mitochondrial molecular clock, American Journal of Human Genetics, 84, 6, 740–759, June 2009, 19500773, 2694979, 10.1016/j.ajhg.2009.05.001, reported a value of 1 mutation every 7884 years dating back to the most recent common ancestor of humans and apes, which is consistent with estimates of mutation rates of autosomal DNA (10−8 per base per generation.JOURNAL, Nachman MW, Crowell SL, Estimate of the mutation rate per nucleotide in humans, Genetics, 156, 1, 297–304, September 2000, 10978293, 1461236,weblink

Dysfunction and disease

Mitochondrial diseases

Damage and subsequent dysfunction in mitochondria is an important factor in a range of human diseases due to their influence in cell metabolism. Mitochondrial disorders often present themselves as neurological disorders, including autism. They can also manifest as myopathy, diabetes, multiple endocrinopathy, and a variety of other systemic disorders.JOURNAL, Zeviani M, Di Donato S, Mitochondrial disorders, Brain, 127, Pt 10, 2153–2172, October 2004, 15358637, 10.1093/brain/awh259, Diseases caused by mutation in the mtDNA include Kearns-Sayre syndrome, MELAS syndrome and Leber's hereditary optic neuropathy.JOURNAL, Taylor RW, Turnbull DM, Mitochondrial DNA mutations in human disease, Nature Reviews. Genetics, 6, 5, 389–402, May 2005, 15861210, 1762815, 10.1038/nrg1606, In the vast majority of cases, these diseases are transmitted by a female to her children, as the zygote derives its mitochondria and hence its mtDNA from the ovum. Diseases such as Kearns-Sayre syndrome, Pearson syndrome, and progressive external ophthalmoplegia are thought to be due to large-scale mtDNA rearrangements, whereas other diseases such as MELAS syndrome, Leber's hereditary optic neuropathy, myoclonic epilepsy with ragged red fibers (MERRF), and others are due to point mutations in mtDNA.In other diseases, defects in nuclear genes lead to dysfunction of mitochondrial proteins. This is the case in Friedreich's ataxia, hereditary spastic paraplegia, and Wilson's disease.JOURNAL, Chinnery PF, Schon EA, Mitochondria, Journal of Neurology, Neurosurgery, and Psychiatry, 74, 9, 1188–1199, September 2003, 12933917, 1738655, 10.1136/jnnp.74.9.1188, These diseases are inherited in a dominance relationship, as applies to most other genetic diseases. A variety of disorders can be caused by nuclear mutations of oxidative phosphorylation enzymes, such as coenzyme Q10 deficiency and Barth syndrome. Environmental influences may interact with hereditary predispositions and cause mitochondrial disease. For example, there may be a link between pesticide exposure and the later onset of Parkinson's disease.JOURNAL, Sherer TB, Betarbet R, Greenamyre JT, Environment, mitochondria, and Parkinson's disease, The Neuroscientist, 8, 3, 192–197, June 2002, 12061498, 10.1177/1073858402008003004, JOURNAL, Gomez C, Bandez MJ, Navarro A, Pesticides and impairment of mitochondrial function in relation with the parkinsonian syndrome, Frontiers in Bioscience, 12, 1079–1093, January 2007, 17127363, 10.2741/2128, Other pathologies with etiology involving mitochondrial dysfunction include schizophrenia, bipolar disorder, dementia, Alzheimer's disease,JOURNAL, Lim YA, Rhein V, Baysang G, Meier F, Poljak A, Raftery MJ, Guilhaus M, Ittner LM, Eckert A, Götz J, Abeta and human amylin share a common toxicity pathway via mitochondrial dysfunction, Proteomics, 10, 8, 1621–1633, April 2010, 20186753, 10.1002/pmic.200900651, Parkinson's disease, epilepsy, stroke, cardiovascular disease, chronic fatigue syndrome, retinitis pigmentosa, and diabetes mellitus.JOURNAL, Schapira AH, Mitochondrial disease, Lancet, 368, 9529, 70–82, July 2006, 16815381, 10.1016/S0140-6736(06)68970-8, JOURNAL, Pieczenik SR, Neustadt J, Mitochondrial dysfunction and molecular pathways of disease, Experimental and Molecular Pathology, 83, 1, 84–92, August 2007, 17239370, 10.1016/j.yexmp.2006.09.008, Mitochondria-mediated oxidative stress plays a role in cardiomyopathy in Type 2 diabetics. Increased fatty acid delivery to the heart increases fatty acid uptake by cardiomyocytes, resulting in increased fatty acid oxidation in these cells. This process increases the reducing equivalents available to the electron transport chain of the mitochondria, ultimately increasing reactive oxygen species (ROS) production. ROS increases uncoupling proteins (UCPs) and potentiate proton leakage through the adenine nucleotide translocator (ANT), the combination of which uncouples the mitochondria. Uncoupling then increases oxygen consumption by the mitochondria, compounding the increase in fatty acid oxidation. This creates a vicious cycle of uncoupling; furthermore, even though oxygen consumption increases, ATP synthesis does not increase proportionally because the mitochondria is uncoupled. Less ATP availability ultimately results in an energy deficit presenting as reduced cardiac efficiency and contractile dysfunction. To compound the problem, impaired sarcoplasmic reticulum calcium release and reduced mitochondrial reuptake limits peak cytosolic levels of the important signaling ion during muscle contraction. The decreased intra-mitochondrial calcium concentration increases dehydrogenase activation and ATP synthesis. So in addition to lower ATP synthesis due to fatty acid oxidation, ATP synthesis is impaired by poor calcium signaling as well, causing cardiac problems for diabetics.JOURNAL, Bugger H, Abel ED, Mitochondria in the diabetic heart, Cardiovascular Research, 88, 2, 229–240, November 2010, 20639213, 2952534, 10.1093/cvr/cvq239,

Possible relationships to aging

Given the role of mitochondria as the cell's powerhouse, there may be some leakage of the high-energy electrons in the respiratory chain to form reactive oxygen species. This was thought to result in significant oxidative stress in the mitochondria with high mutation rates of mitochondrial DNA (mtDNA).JOURNAL, Richter C, Park JW, Ames BN, Normal oxidative damage to mitochondrial and nuclear DNA is extensive, Proceedings of the National Academy of Sciences of the United States of America, 85, 17, 6465–6467, September 1988, 3413108, 281993, 10.1073/pnas.85.17.6465, 1988PNAS...85.6465R, Hypothesized links between aging and oxidative stress are not new and were proposed in 1956,JOURNAL, Harman D, Aging: a theory based on free radical and radiation chemistry, Journal of Gerontology, 11, 3, 298–300, July 1956, 13332224, 10.1093/geronj/11.3.298,, which was later refined into the mitochondrial free radical theory of aging.JOURNAL, Harman D, The biologic clock: the mitochondria?, Journal of the American Geriatrics Society, 20, 4, 145–147, April 1972, 5016631, 10.1111/j.1532-5415.1972.tb00787.x, A vicious cycle was thought to occur, as oxidative stress leads to mitochondrial DNA mutations, which can lead to enzymatic abnormalities and further oxidative stress.A number of changes can occur to mitochondria during the aging process.WEB,weblink Mitochondria and Aging,, Tissues from elderly patients show a decrease in enzymatic activity of the proteins of the respiratory chain.JOURNAL, Boffoli D, Scacco SC, Vergari R, Solarino G, Santacroce G, Papa S, Decline with age of the respiratory chain activity in human skeletal muscle, Biochimica et Biophysica Acta, 1226, 1, 73–82, April 1994, 8155742, 10.1016/0925-4439(94)90061-2, However, mutated mtDNA can only be found in about 0.2% of very old cells.JOURNAL, de Grey AD, Mitochondrial mutations in mammalian aging: an over-hasty about-turn?, Rejuvenation Research, 7, 3, 171–174, 2004, 15588517, 10.1089/rej.2004.7.171, Large deletions in the mitochondrial genome have been hypothesized to lead to high levels of oxidative stress and neuronal death in Parkinson's disease.JOURNAL, Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH, Jaros E, Hersheson JS, Betts J, Klopstock T, Taylor RW, Turnbull DM, High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease, Nature Genetics, 38, 5, 515–517, May 2006, 16604074, 10.1038/ng1769,

In popular culture

Madeleine L'Engle's 1973 science fantasy novel A Wind in the Door prominently features the mitochondria of main character Charles Wallace Murry, as being inhabited by creatures known as the farandolae. The novel also features other characters travelling inside one of Murry's mitochondria.The 1995 horror fiction novel Parasite Eve by Hideaki Sena depicts mitochondria as having some consciousness and mind control abilities, attempting to use these to overtake eukaryotes as the dominant life form. This text was adapted into an eponymous film, video game, and video game sequel all involving a similar premise.In the Star Wars franchise, microorganisms referred to as "midi-chlorians" give some characters the ability to sense and use the Force. George Lucas, director of the 1999 film (Star Wars: Episode I – The Phantom Menace), in which midi-chlorians were introduced, described them as "a loose depiction of mitochondria".JOURNAL,weblink 20,000 Per Cell: Why Midi-chlorians Suck, Narcisse, Evan, vanc, August 10, 2010, Time (magazine), Time, June 19, 2016, The non-fictional bacteria genus Midichloria was later named after the midi-chlorians of Star Wars.As a result of the mitochondrion's prominence in modern American science education, the phrase "the mitochondria is the powerhouse of the cell" became an internet meme.WEB,weblink So, Mitochondria Aren't Actually The Powerhouse Of The Cell After All, Byrne, Nathan, vanc, May 13, 2016, Newsy, June 19, 2016,

See also

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External links

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