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autophagy
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{{about|the cellular process}}(File:Autophagy diagram PLoS Biology.jpg|thumb|right|(A) Diagram of the process of autophagy, which produces the structures autophagosomes, AP, and autolysomes, AL; (B) Electron micrograph of autophagic structures AP and AL in the fatbody of a fruit fly larva; (C) Fluorescently labeled autophagosomes AP in liver cells of starved mice.)Autophagy (or autophagocytosis) (from the Ancient Greek autóphagos, meaning "self-devouring"WEB,weblink Henry George Liddell, Henry Liddell, Robert Scott, Robert Scott (philologist), Henry Stuart Jones, Henry Stuart Jones, A Greek–English Lexicon, tufts.edu, αὐτό-φαγος, 6 September 2018, and kýtos, meaning "hollow"WEB,weblink Henry George Liddell, Henry Liddell, Robert Scott, Robert Scott (philologist), Henry Stuart Jones, Henry Stuart Jones, A Greek–English Lexicon, tufts.edu, 6 September 2018, κύτος, ) is the natural, regulated mechanism of the cell that disassembles unnecessary or dysfunctional components.JOURNAL, Klionsky DJ, Autophagy revisited: a conversation with Christian de Duve, Autophagy, 4, 6, 740–3, August 2008, 18567941, 10.4161/auto.6398, It allows the orderly degradation and recycling of cellular components.JOURNAL, Mizushima N, Komatsu M, November 2011, Autophagy: renovation of cells and tissues, Cell, 147, 4, 728–41, 10.1016/j.cell.2011.10.026, 22078875, JOURNAL, Kobayashi S, 2015, Choose Delicately and Reuse Adequately: The Newly Revealed Process of Autophagy, Biological & Pharmaceutical Bulletin, 38, 8, 1098–103, 10.1248/bpb.b15-00096, 26235572, Three forms of autophagy are commonly described: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). In macroautophagy, expendable cytoplasmic constituents are targeted and isolated from the rest of the cell within a double-membraned vesicle known as an autophagosome,JOURNAL, Mizushima N, Yoshimori T, Ohsumi Y, The role of Atg proteins in autophagosome formation, Annual Review of Cell and Developmental Biology, 27, 1, 107–32, 10 November 2011, 21801009, 10.1146/annurev-cellbio-092910-154005, JOURNAL, Xie Z, Klionsky DJ, Autophagosome formation: core machinery and adaptations, Nature Cell Biology, 9, 10, 1102–9, October 2007, 17909521, 10.1038/ncb1007-1102, which, in time, fuses with an available lysosome, bringing its specialty process of waste management and disposal; and eventually the contents of the vesicle (now called an autolysosome) are degraded and recycled.In disease, autophagy has been seen as an adaptive response to stress, promoting survival of the cell; but in other cases it appears to promote cell death and morbidity. In the extreme case of starvation, the breakdown of cellular components promotes cellular survival by maintaining cellular energy levels.The name "autophagy" was coined by Belgian biochemist Christian de Duve in 1963 based on his discovery of the functions of lysosome. The identification of autophagy-related genes in yeast in the 1990s allowed researchers to deduce the mechanisms of autophagy,JOURNAL, Klionsky DJ, Cueva R, Yaver DS, Aminopeptidase I of Saccharomyces cerevisiae is localized to the vacuole independent of the secretory pathway, The Journal of Cell Biology, 119, 2, 287–99, October 1992, 1400574, 2289658, 10.1083/jcb.119.2.287, JOURNAL, Takeshige K, Baba M, Tsuboi S, Noda T, Ohsumi Y, Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction, The Journal of Cell Biology, 119, 2, 301–11, October 1992, 1400575, 2289660, 10.1083/jcb.119.2.301, JOURNAL, Thumm M, Egner R, Koch B, Schlumpberger M, Straub M, Veenhuis M, Wolf DH, Isolation of autophagocytosis mutants of Saccharomyces cerevisiae, FEBS Letters, 349, 2, 275–80, August 1994, 8050581, 10.1016/0014-5793(94)00672-5, JOURNAL, Tsukada M, Ohsumi Y, Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae, FEBS Letters, 333, 1–2, 169–74, October 1993, 8224160, 10.1016/0014-5793(93)80398-e, JOURNAL, Harding TM, Morano KA, Scott SV, Klionsky DJ, Isolation and characterization of yeast mutants in the cytoplasm to vacuole protein targeting pathway, The Journal of Cell Biology, 131, 3, 591–602, November 1995, 7593182, 2120622, 10.1083/jcb.131.3.591, which eventually led to the award of the 2016 Nobel Prize in Physiology or Medicine to Japanese researcher Yoshinori Ohsumi.WEB,weblink The Nobel Prize in Physiology or Medicine 2016, The Nobel Foundation, 3 October 2016, 3 October 2016,

History

Autophagy was first observed by Keith R. Porter and his student Thomas Ashford at the Rockefeller Institute. In January 1962 they reported an increased number of lysosomes in rat liver cells after the addition of glucagon, and that some displaced lysosomes towards the centre of the cell contained other cell organelles such as mitochondria. They called this autolysis after Christian de Duve and Alex B. Novikoff. However Porter and Ashford wrongly interpreted their data as lysosome formation (ignoring the pre-existing organelles). Lysosomes could not be cell organelles, but part of cytoplasm such as mitochondria, and that hydrolytic enzymes were produced by microbodies.JOURNAL, Ashford TP, Porter KR, Cytoplasmic components in hepatic cell lysosomes, The Journal of Cell Biology, 12, 1, 198–202, January 1962, 13862833, 2106008, 10.1083/jcb.12.1.198, In 1963 Hruban, Spargo and colleagues published a detailed ultrastructural description of "focal cytoplasmic degradation," which referenced a 1955 German study of injury-induced sequestration. Hruban, Spargo and colleagues recognized three continuous stages of maturation of the sequestered cytoplasm to lysosomes, and that the process was not limited to injury states that functioned under physiological conditions for "reutilization of cellular materials," and the "disposal of organelles" during differentiation.JOURNAL, Hruban Z, Spargo B, Swift H, Wissler RW, Kleinfeld RG, Focal cytoplasmic degradation, The American Journal of Pathology, 42, 6, 657–83, June 1963, 13955261, 1949709, Inspired by this discovery, de Duve christened the phenomena "autophagy". Unlike Porter and Ashford, de Duve conceived the term as a part of lysosomal function while describing the role of glucagon as a major inducer of cell degradation in the liver. With his student Russell Deter, he established that lysosomes are responsible for glucagon-induced autophagy.JOURNAL, Deter RL, Baudhuin P, De Duve C, Participation of lysosomes in cellular autophagy induced in rat liver by glucagon, The Journal of Cell Biology, 35, 2, C11–6, November 1967, 6055998, 2107130, 10.1083/jcb.35.2.c11, JOURNAL, Deter RL, De Duve C, Influence of glucagon, an inducer of cellular autophagy, on some physical properties of rat liver lysosomes, The Journal of Cell Biology, 33, 2, 437–49, May 1967, 4292315, 2108350, 10.1083/jcb.33.2.437, This was the first time the fact that lysosomes are the sites of intracellular autophagy was established.JOURNAL, de Duve C, Lysosomes revisited, European Journal of Biochemistry, 137, 3, 391–7, December 1983, 6319122, 10.1111/j.1432-1033.1983.tb07841.x, BOOK, William A., Dunn, Laura A., Schroder, John P., Aris, vanc, Historical overview of autophagy, Hong-Gang, Wang, Autophagy and Cancer, 2013,weblink 3–4, Springer, 9781461465614, In the 1990s several groups of scientists independently discovered autophagy-related genes using the budding yeast. Notably, Yoshinori Ohsumi and Michael Thumm examined starvation-induced non-selective autophagy; in the meantime, Daniel J Klionsky discovered the cytoplasm-to-vacuole targeting (CVT) pathway, which is a form of selective autophagy. They soon found that they were in fact looking at essentially the same pathway, just from different angles.JOURNAL, Harding TM, Hefner-Gravink A, Thumm M, Klionsky DJ, Genetic and phenotypic overlap between autophagy and the cytoplasm to vacuole protein targeting pathway, The Journal of Biological Chemistry, 271, 30, 17621–4, July 1996, 8663607, 10.1074/jbc.271.30.17621, JOURNAL, Scott SV, Hefner-Gravink A, Morano KA, Noda T, Ohsumi Y, Klionsky DJ, Cytoplasm-to-vacuole targeting and autophagy employ the same machinery to deliver proteins to the yeast vacuole, Proceedings of the National Academy of Sciences of the United States of America, 93, 22, 12304–8, October 1996, 8901576, 37986, 10.1073/pnas.93.22.12304, Initially, the genes discovered by these and other yeast groups were given different names (APG, AUT, CVT, GSA, PAG, PAZ, and PDD). A unified nomenclature was advocated in 2003 by the yeast researchers to use ATG to denote autophagy genes.JOURNAL, Klionsky DJ, Cregg JM, Dunn WA, Emr SD, Sakai Y, Sandoval IV, Sibirny A, Subramani S, Thumm M, Veenhuis M, Ohsumi Y, A unified nomenclature for yeast autophagy-related genes, Developmental Cell, 5, 4, 539–45, October 2003, 14536056, 10.1016/s1534-5807(03)00296-x, The 2016 Nobel Prize in Physiology or Medicine was awarded to Yoshinori Ohsumi, although some have pointed out that the award could have been more inclusive.JOURNAL, Van Noorden R, Ledford H, Medicine Nobel for research on how cells 'eat themselves', Nature, 538, 7623, 18–19, October 2016, 27708326, 10.1038/nature.2016.20721, The field of autophagy research experienced accelerated growth at the turn of the 21st century. Knowledge of ATG genes provided scientists more convenient tools to dissect functions of autophagy in human health and disease. In 1999, a landmark discovery connecting autophagy with cancer was published by Beth Levine's group.JOURNAL, Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B, Induction of autophagy and inhibition of tumorigenesis by beclin 1, Nature, 402, 6762, 672–6, December 1999, 10604474, 10.1038/45257, To this date, relationship between cancer and autophagy continues to be a main theme of autophagy research. The roles of autophagy in neurodegeneration and immune defense also received considerable attention. In 2003, the first Gordon Research Conference on autophagy was held at Waterville.WEB, Autophagy in Stress, Development & Disease, 2003, Gordon Research Conference,weblink In 2005, Daniel J Klionsky launched Autophagy, a scientific journal dedicated to this field. The first Keystone Symposia Conference on autophagy was held in 2007 at Monterey.WEB, Autophagy in Health and Disease (Z3), 2007, Keystone Symposia on Molecular and Cellular Biology,weblink In 2008, Carol A Mercer created a BHMT fusion protein (GST-BHMT), which showed starvation-induced site-specific fragmentation in cell lines. The degradation of betaine homo-cysteine methyltransferase (BHMT), a metabolic enzyme, could be used to assess autophagy flux in mammalian cells.

Process and pathways

There are three main types of autophagy, namely macroautophagy, microautophagy and Chaperone mediated autophagy. They are mediated by the autophagy-related genes and their associated enzymes.JOURNAL, Lee J, Giordano S, Zhang J, Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling, The Biochemical Journal, 441, 2, 523–40, January 2012, 22187934, 3258656, 10.1042/BJ20111451,weblink JOURNAL, Mizushima N, Ohsumi Y, Yoshimori T, Autophagosome formation in mammalian cells, Cell Structure and Function, 27, 6, 421–9, December 2002, 12576635, 10.1247/csf.27.421, JOURNAL, Youle RJ, Narendra DP, Mechanisms of mitophagy, Nature Reviews. Molecular Cell Biology, 12, 1, 9–14, January 2011, 21179058, 4780047, 10.1038/nrm3028, Macroautophagy is then divided into bulk and selective autophagy. In the selective autophagy is the autophagy of organelles; mitophagy,JOURNAL, Ding WX, Yin XM, Mitophagy: mechanisms, pathophysiological roles, and analysis, Biological Chemistry, 393, 7, 547–64, July 2012, 22944659, 3630798, 10.1515/hsz-2012-0119, lipophagy, pexophagy,JOURNAL, Till A, Lakhani R, Burnett SF, Subramani S, Pexophagy: the selective degradation of peroxisomes, International Journal of Cell Biology, 2012, 512721, 2012, 22536249, 3320016, 10.1155/2012/512721, chlorophagy,JOURNAL, Lei L, Chlorophagy: Preventing sunburn, Nature Plants, 3, 3, 17026, March 2017, 28248315, 10.1038/nplants.2017.26, ribophagyJOURNAL, An H, Harper JW, Systematic analysis of ribophagy in human cells reveals bystander flux during selective autophagy, Nature Cell Biology, 20, 2, 135–143, February 2018, 29230017, 5786475, 10.1038/s41556-017-0007-x, and others.Macroautophagy is the main pathway, used primarily to eradicate damaged cell organelles or unused proteins.JOURNAL, Levine B, Mizushima N, Virgin HW, Autophagy in immunity and inflammation, Nature, 469, 7330, 323–35, January 2011, 21248839, 3131688, 10.1038/nature09782, First the phagophore engulfs the material that needs to be degraded, which forms a double membrane known as an autophagosome, around the organelle marked for destruction.JOURNAL, Česen MH, Pegan K, Spes A, Turk B, Lysosomal pathways to cell death and their therapeutic applications, Experimental Cell Research, 318, 11, 1245–51, July 2012, 22465226, 10.1016/j.yexcr.2012.03.005, The autophagosome then travels through the cytoplasm of the cell to a lysosome, and the two organelles fuse. Within the lysosome, the contents of the autophagosome are degraded via acidic lysosomal hydrolase.JOURNAL,weblink" title="web.archive.org/web/20120801130843weblink">weblink 2012-08-01,weblink 2011, Homma, K.S., List of autophagy-related proteins and 3D structures, Autophagy Database, 290, 2012-10-08, {{inconsistent citations, }}Microautophagy, on the other hand, involves the direct engulfment of cytoplasmic material into the lysosome.JOURNAL, The Discovery of Lysosomes and Autophagy, Nature Education, 49, 3, 2010, Castro-Obregon, Susana, 9,weblink This occurs by invagination, meaning the inward folding of the lysosomal membrane, or cellular protrusion.Chaperone-mediated autophagy, or CMA, is a very complex and specific pathway, which involves the recognition by the hsc70-containing complex.JOURNAL, Bandyopadhyay U, Kaushik S, Varticovski L, Cuervo AM, The chaperone-mediated autophagy receptor organizes in dynamic protein complexes at the lysosomal membrane, Molecular and Cellular Biology, 28, 18, 5747–63, September 2008, 18644871, 2546938, 10.1128/MCB.02070-07, This means that a protein must contain the recognition site for this hsc70 complex which will allow it to bind to this chaperone, forming the CMA- substrate/chaperone complex. This complex then moves to the lysosomal membrane-bound protein that will recognise and bind with the CMA receptor, allowing it to enter the cell.{{citation needed|date=September 2018}} Upon recognition, the substrate protein gets unfolded and it is translocated across the lysosome membrane with the assistance of the lysosomal hsc70 chaperone. CMA is significantly different from other types of autophagy because it translocates protein material in a one by one manner, and it is extremely selective about what material crosses the lysosomal barrier.Mitophagy is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. Mitophagy promotes turnover of mitochondria and prevents accumulation of dysfunctional mitochondria which can lead to cellular degeneration. It is mediated by Atg32 (in yeast) and NIX and its regulator BNIP3 in mammals. Mitophagy is regulated by PINK1 and parkin proteins. The occurrence of mitophagy is not limited to the damaged mitochondria but also involves undamaged ones.Lipophagy is the degradation of lipids by autophagy,JOURNAL, Liu K, Czaja MJ, Regulation of lipid stores and metabolism by lipophagy, Cell Death and Differentiation, 20, 1, 3–11, January 2013, 22595754, 10.1038/cdd.2012.63, 3524634, a function which has been shown to exist in both animal and fungal cells.JOURNAL, Ward C, Martinez-Lopez N, Otten EG, Carroll B, Maetzel D, Singh R, Sarkar S, Korolchuk VI, Autophagy, lipophagy and lysosomal lipid storage disorders, Biochimica et Biophysica Acta, 1861, 4, 269–84, April 2016, 26778751, 10.1016/j.bbalip.2016.01.006, The role of lipophagy in plant cells, however, remains elusive.JOURNAL, Elander PH, Minina EA, Bozhkov PV, Autophagy in turnover of lipid stores: trans-kingdom comparison, Journal of Experimental Botany, 69, 6, 1301–1311, March 2018, 29309625, 10.1093/jxb/erx433, In lipophagy the target are lipid structures called lipid droplets (LDs), spheric "organelles" with a core of mainly triacylglycerols (TAGs) and a unilayer of phospholipids and membrane proteins. In animal cells the main lipophagic pathway is via the engulfment of LDs by the phagophore, macroautophagy. In fungal cells on the other hand microplipophagy constitutes the main pathway and is especially well studied in the budding yeast Saccharomyces cerevisiaeJOURNAL, van Zutphen T, Todde V, de Boer R, Kreim M, Hofbauer HF, Wolinski H, Veenhuis M, van der Klei IJ, Kohlwein SD, Lipid droplet autophagy in the yeast Saccharomyces cerevisiae, Molecular Biology of the Cell, 25, 2, 290–301, January 2014, 24258026, 3890349, 10.1091/mbc.E13-08-0448, . Lipophagy was first discovered in mice and published 2009.JOURNAL, Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM, Czaja MJ, Autophagy regulates lipid metabolism, Nature, 458, 7242, 1131–5, April 2009, 19339967, 2676208, 10.1038/nature07976,

Molecular biology

Autophagy is executed by autophagy-related (Atg) genes. Prior to 2003, ten or more names were used, but after this point a unified nomenclature was devised by fungal autophagy researchers.JOURNAL, Klionsky DJ, Look people, "Atg" is an abbreviation for "autophagy-related." That's it, Autophagy, 8, 9, 1281–2, September 2012, 22889836, 3442874, 10.4161/auto.21812, Atg or ATG stands for autophagy related. It does not specify gene or a protein.The first autophagy genes were identified by genetic screens conducted in Saccharomyces cerevisiae. Following their identification those genes were functionally characterized and their orthologs in a variety of different organisms were identified and studied.JOURNAL, Lamb CA, Yoshimori T, Tooze SA, The autophagosome: origins unknown, biogenesis complex, Nature Reviews. Molecular Cell Biology, 14, 12, 759–74, December 2013, 24201109, 10.1038/nrm3696, In mammals, amino acid sensing and additional signals such as growth factors and reactive oxygen species regulate the activity of the protein kinases mTOR and AMPK.JOURNAL, Russell RC, Yuan HX, Guan KL, Autophagy regulation by nutrient signaling, Cell Research, 24, 1, 42–57, January 2014, 24343578, 3879708, 10.1038/cr.2013.166, These two kinases regulate autophagy through inhibitory phosphorylation of the Unc-51-like kinases ULK1 and ULK2 (mammalian homologues of Atg1).JOURNAL, Chan EY, Regulation and function of uncoordinated-51 like kinase proteins, Antioxidants & Redox Signaling, 17, 5, 775–85, September 2012, 22074133, 10.1089/ars.2011.4396, Induction of autophagy results in the dephosphorylation and activation of the ULK kinases. ULK is part of a protein complex containing Atg13, Atg101 and FIP200. ULK phosphorylates and activates Beclin-1 (mammalian homologue of Atg6),JOURNAL, Russell RC, Tian Y, Yuan H, Park HW, Chang YY, Kim J, Kim H, Neufeld TP, Dillin A, Guan KL, ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase, Nature Cell Biology, 15, 7, 741–50, July 2013, 23685627, 3885611, 10.1038/ncb2757, which is also part of a protein complex. The autophagy-inducible Beclin-1 complexJOURNAL, Itakura E, Kishi C, Inoue K, Mizushima N, Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG, Molecular Biology of the Cell, 19, 12, 5360–72, December 2008, 18843052, 2592660, 10.1091/mbc.E08-01-0080, contains the proteins p150, Atg14L and the class III phosphatidylinositol 3-phosphate kinase (PI(3)K) Vps34.JOURNAL, Kang R, Zeh HJ, Lotze MT, Tang D, The Beclin 1 network regulates autophagy and apoptosis, Cell Death and Differentiation, 18, 4, 571–80, April 2011, 21311563, 3131912, 10.1038/cdd.2010.191, The active ULK and Beclin-1 complexes re-localize to the site of autophagosome initiation, the phagophore, where they both contribute to the activation of downstream autophagy components.JOURNAL, Di Bartolomeo S, Corazzari M, Nazio F, Oliverio S, Lisi G, Antonioli M, Pagliarini V, Matteoni S, Fuoco C, Giunta L, D'Amelio M, Nardacci R, Romagnoli A, Piacentini M, Cecconi F, Fimia GM, The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy, The Journal of Cell Biology, 191, 1, 155–68, October 2010, 20921139, 2953445, 10.1083/jcb.201002100, JOURNAL, Hara T, Takamura A, Kishi C, Iemura S, Natsume T, Guan JL, Mizushima N, FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells, The Journal of Cell Biology, 181, 3, 497–510, May 2008, 18443221, 2364687, 10.1083/jcb.200712064, Once active, VPS34 phosphorylates the lipid phosphatidylinositol to generate phosphatidylinositol 3-phosphate (PtdIns(3)P) on the surface of the phagophore. The generated PtdIns(3)P is used as a docking point for proteins harboring a PtdIns(3)P binding motif. WIPI2, a PtdIns(3)P binding protein of the WIPI (WD-repeat protein interacting with phosphoinositides) protein family, was recently shown to physically bind Atg16L1.T. Proikas-Cezanne, Z. Takacs, P. Donnes, and O. Kohlbacher, 'Wipi Proteins: Essential Ptdins3p Effectors at the Nascent Autophagosome', J Cell Sci, 128 (2015), 207-17 Atg16L1 is a member of an E3-like protein complex involved in one of two ubiquitin-like conjugation systems essential for autophagosome formation. Its binding by WIPI2 recruits it to the phagophore and mediates its activity.JOURNAL, Dooley HC, Razi M, Polson HE, Girardin SE, Wilson MI, Tooze SA, WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1, Molecular Cell, 55, 2, 238–52, July 2014, 24954904, 4104028, 10.1016/j.molcel.2014.05.021, The first of the two ubiquitin-like conjugation systems involved in autophagy covalently binds the ubiquitin-like protein Atg12 to Atg5. The resulting conjugate protein then binds Atg16L1 to form an E3-like complex which functions as part of the second ubiquitin-like conjugation system.JOURNAL, Hanada T, Noda NN, Satomi Y, Ichimura Y, Fujioka Y, Takao T, Inagaki F, Ohsumi Y, The Atg12-Atg5 conjugate has a novel E3-like activity for protein lipidation in autophagy, The Journal of Biological Chemistry, 282, 52, 37298–302, December 2007, 17986448, 10.1074/jbc.C700195200, This complex binds and activates Atg3, which covalently attaches mammalian homologues of the ubiquitin-like yeast protein ATG8 (LC3A-C, GATE16, and GABARAPL1-3), the most studied being LC3 proteins, to the lipid phosphatidylethanolamine (PE) on the surface of autophagosomes.JOURNAL, Kabeya Y, Mizushima N, Yamamoto A, Oshitani-Okamoto S, Ohsumi Y, Yoshimori T, LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation, Journal of Cell Science, 117, Pt 13, 2805–12, June 2004, 15169837, 10.1242/jcs.01131, Lipidated LC3 contributes to the closure of autophagosomes,JOURNAL, Fujita N, Hayashi-Nishino M, Fukumoto H, Omori H, Yamamoto A, Noda T, Yoshimori T, An Atg4B mutant hampers the lipidation of LC3 paralogues and causes defects in autophagosome closure, Molecular Biology of the Cell, 19, 11, 4651–9, November 2008, 18768752, 2575160, 10.1091/mbc.e08-03-0312, and enables the docking of specific cargos and adaptor proteins such as Sequestosome-1/p62.JOURNAL, Park S, Choi SG, Yoo SM, Son JH, Jung YK, Choline dehydrogenase interacts with SQSTM1/p62 to recruit LC3 and stimulate mitophagy, Autophagy, 10, 11, 1906–20, 2014, 25483962, 4502719, 10.4161/auto.32177, The completed autophagosome then fuses with a lysosome through the actions of multiple proteins, including SNAREsJOURNAL, Fader CM, Sánchez DG, Mestre MB, Colombo MI, TI-VAMP/VAMP7 and VAMP3/cellubrevin: two v-SNARE proteins involved in specific steps of the autophagy/multivesicular body pathways, Biochimica et Biophysica Acta, 1793, 12, 1901–16, December 2009, 19781582, 10.1016/j.bbamcr.2009.09.011, JOURNAL, Furuta N, Fujita N, Noda T, Yoshimori T, Amano A, Combinational soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins VAMP8 and Vti1b mediate fusion of antimicrobial and canonical autophagosomes with lysosomes, Molecular Biology of the Cell, 21, 6, 1001–10, March 2010, 20089838, 2836953, 10.1091/mbc.e09-08-0693, and UVRAG.JOURNAL, Kim YM, Jung CH, Seo M, Kim EK, Park JM, Bae SS, Kim DH, mTORC1 phosphorylates UVRAG to negatively regulate autophagosome and endosome maturation, Molecular Cell, 57, 2, 207–18, January 2015, 25533187, 4304967, 10.1016/j.molcel.2014.11.013, JOURNAL, Liang C, Lee JS, Inn KS, Gack MU, Li Q, Roberts EA, Vergne I, Deretic V, Feng P, Akazawa C, Jung JU, Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking, Nature Cell Biology, 10, 7, 776–87, July 2008, 18552835, 2878716, 10.1038/ncb1740, Following the fusion LC3 is retained on the vesicle's inner side and degraded along with the cargo, while the LC3 molecules attached to the outer side are cleaved off by Atg4 and recycled.JOURNAL, Satoo K, Noda NN, Kumeta H, Fujioka Y, Mizushima N, Ohsumi Y, Inagaki F, The structure of Atg4B-LC3 complex reveals the mechanism of LC3 processing and delipidation during autophagy, The EMBO Journal, 28, 9, 1341–50, May 2009, 19322194, 2683054, 10.1038/emboj.2009.80, The contents of the autolysosome are subsequently degraded and their building blocks are released from the vesicle through the action of permeases.JOURNAL, Yang Z, Huang J, Geng J, Nair U, Klionsky DJ, Atg22 recycles amino acids to link the degradative and recycling functions of autophagy, Molecular Biology of the Cell, 17, 12, 5094–104, December 2006, 17021250, 1679675, 10.1091/mbc.e06-06-0479,

Functions

Nutrient starvation

Autophagy has roles in various cellular functions. One particular example is in yeasts, where the nutrient starvation induces a high level of autophagy. This allows unneeded proteins to be degraded and the amino acids recycled for the synthesis of proteins that are essential for survival.JOURNAL, Reggiori F, Klionsky DJ, Autophagy in the eukaryotic cell, Eukaryotic Cell, 1, 1, 11–21, February 2002, 12455967, 118053, 10.1128/EC.01.1.11-21.2002, JOURNAL, Klionsky DJ, Emr SD, Autophagy as a regulated pathway of cellular degradation, Science, 290, 5497, 1717–21, December 2000, 11099404, 10.1126/science.290.5497.1717, 2732363, JOURNAL, Levine B, Klionsky DJ, Development by self-digestion: molecular mechanisms and biological functions of autophagy, Developmental Cell, 6, 4, 463–77, April 2004, 15068787, 10.1016/S1534-5807(04)00099-1, In higher eukaryotes, autophagy is induced in response to the nutrient depletion that occurs in animals at birth after severing off the trans-placental food supply, as well as that of nutrient starved cultured cells and tissues.JOURNAL, Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T, Mizushima N, The role of autophagy during the early neonatal starvation period, Nature, 432, 7020, 1032–6, December 2004, 15525940, 10.1038/nature03029, etal, JOURNAL, Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y, In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker, Molecular Biology of the Cell, 15, 3, 1101–11, March 2004, 14699058, 363084, 10.1091/mbc.E03-09-0704, Mutant yeast cells that have a reduced autophagic capability rapidly perish in nutrition-deficient conditions.JOURNAL, Tsukada M, Ohsumi Y, Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae, FEBS Letters, 333, 1–2, 169–74, October 1993, 8224160, 10.1016/0014-5793(93)80398-E, Studies on the apg mutants suggest that autophagy via autophagic bodies is indispensable for protein degradation in the vacuoles under starvation conditions, and that at least 15 APG genes are involved in autophagy in yeast. A gene known as ATG7 has been implicated in nutrient-mediated autophagy, as mice studies have shown that starvation-induced autophagy was impaired in atg7-deficient mice.

Xenophagy

In microbiology, xenophagy is the autophagic degradation of infectious particles. Cellular autophagic machinery also play an important role in innate immunity. Intracellular pathogens, such as Mycobacterium tuberculosis (the bacterium which is responsible for tuberculosis) are targeted for degradation by the same cellular machinery and regulatory mechanisms that target host mitochondria for degradation.JOURNAL, Gutierrez MG, Master SS, Singh SB, Taylor GA, Colombo MI, Deretic V, Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages, Cell, 119, 6, 753–66, December 2004, 15607973, 10.1016/j.cell.2004.11.038, Incidentally, this is further evidence for the endosymbiotic hypothesis. This process generally leads to the destruction of the invasive microorganism, although some bacteria can block the maturation of phagosomes into degradative organelles called phagolysosomes.BOOK, Deretic V, Delgado M, Vergne I, Master S, De Haro S, Ponpuak M, Singh S, Autophagy in immunity against mycobacterium tuberculosis: a model system to dissect immunological roles of autophagy, 335, 169–88, 2009, 19802565, 2788935, 10.1007/978-3-642-00302-8_8, 978-3-642-00301-1, Current Topics in Microbiology and Immunology, Autophagy in Infection and Immunity, Stimulation of autophagy in infected cells can help overcome this phenomenon, restoring pathogen degradation.

Infection

Vesicular stomatitis virus is believed to be taken up by the autophagosome from the cytosol and translocated to the endosomes where detection takes place by a pattern recognition receptor called toll-like receptor 7, detecting single stranded RNA. Following activation of the toll-like receptor, intracellular signaling cascades are initiated, leading to induction of interferon and other antiviral cytokines. A subset of viruses and bacteria subvert the autophagic pathway to promote their own replication.JOURNAL, Jackson WT, Giddings TH, Taylor MP, Mulinyawe S, Rabinovitch M, Kopito RR, Kirkegaard K, Subversion of cellular autophagosomal machinery by RNA viruses, PLoS Biology, 3, 5, e156, May 2005, 15884975, 1084330, 10.1371/journal.pbio.0030156, {{open access}} Galectin-8 has recently been identified as an intracellular "danger receptor", able to initiate autophagy against intracellular pathogens. When galectin-8 binds to a damaged vacuole, it recruits an autophagy adaptor such as NDP52 leading to the formation of an autophagosome and bacterial degradation.JOURNAL, Thurston TL, Wandel MP, von Muhlinen N, Foeglein A, Randow F, Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion, Nature, 482, 7385, 414–8, January 2012, 22246324, 3343631, 10.1038/nature10744,

Repair mechanism

Autophagy degrades damaged organelles, cell membranes and proteins, and electing against autophagy is thought to be one of the main reasons for the accumulation of damaged cells and aging.JOURNAL, Cuervo AM, Bergamini E, Brunk UT, Dröge W, Ffrench M, Terman A, Autophagy and aging: the importance of maintaining "clean" cells, Autophagy, 1, 3, 131–40, 2005, 16874025, 10.4161/auto.1.3.2017, Autophagy and autophagy regulators are involved in response to lysosomal damage, often directed by galectins such as galectin-3 and galectin-8, which in turn recruit receptors such as TRIM16.JOURNAL, Chauhan S, Kumar S, Jain A, Ponpuak M, Mudd MH, Kimura T, Choi SW, Peters R, Mandell M, Bruun JA, Johansen T, Deretic V, TRIMs and Galectins Globally Cooperate and TRIM16 and Galectin-3 Co-direct Autophagy in Endomembrane Damage Homeostasis, Developmental Cell, 39, 1, 13–27, October 2016, 27693506, 5104201, 10.1016/j.devcel.2016.08.003, and NDP52 plus directly affect mTOR and AMPK activity, whereas mTOR and AMPK inhibit and activate autophagy, respectivelyJOURNAL, Jia J, Abudu YP, Claude-Taupin A, Gu Y, Kumar S, Choi SW, Peters R, Mudd MH, Allers L, Salemi M, Phinney B, Johansen T, Deretic V, Galectins Control mTOR in Response to Endomembrane Damage, English, Molecular Cell, 70, 1, 120–135.e8, April 2018, 29625033, 5911935, 10.1016/j.molcel.2018.03.009,

Programmed cell death

One of the mechanisms of programmed cell death (PCD) is associated with the appearance of autophagosomes and depends on autophagy proteins. This form of cell death most likely corresponds to a process that has been morphologically defined as autophagic PCD. One question that constantly arises, however, is whether autophagic activity in dying cells is the cause of death or is actually an attempt to prevent it. Morphological and histochemical studies so far did not prove a causative relationship between the autophagic process and cell death. In fact, there have recently been strong arguments that autophagic activity in dying cells might actually be a survival mechanism.BOOK, Tavassoly, Iman, vanc, Dynamics of Cell Fate Decision Mediated by the Interplay of Autophagy and Apoptosis in Cancer Cells, 2015, Springer International Publishing, 978-3-319-14962-2, 10.1007/978-3-319-14962-2, Springer Theses, JOURNAL, Tsujimoto Y, Shimizu S, Another way to die: autophagic programmed cell death, Cell Death and Differentiation, 12 Suppl 2, Suppl 2, 1528–34, November 2005, 16247500, 10.1038/sj.cdd.4401777, Studies of the metamorphosis of insects have shown cells undergoing a form of PCD that appears distinct from other forms; these have been proposed as examples of autophagic cell death.JOURNAL, Schwartz LM, Smith SW, Jones ME, Osborne BA, Do all programmed cell deaths occur via apoptosis?, Proceedings of the National Academy of Sciences of the United States of America, 90, 3, 980–4, February 1993, 8430112, 45794, 10.1073/pnas.90.3.980, Recent pharmacological and biochemical studies have proposed that survival and lethal autophagy can be distinguished by the type and degree of regulatory signaling during stress particularly after viral infection.JOURNAL, Datan E, Shirazian A, Benjamin S, Matassov D, Tinari A, Malorni W, Lockshin RA, Garcia-Sastre A, Zakeri Z, mTOR/p70S6K signaling distinguishes routine, maintenance-level autophagy from autophagic cell death during influenza A infection, Virology, 452-453, March 2014, 175–190, March 2014, 24606695, 4005847, 10.1016/j.virol.2014.01.008, Although promising, these findings have not been examined in non-viral systems.

Exercise

Autophagy is essential for basal homeostasis; it is also extremely important in maintaining muscle homeostasis during physical exercise.JOURNAL, He C, Bassik MC, Moresi V, Sun K, Wei Y, Zou Z, An Z, Loh J, Fisher J, Sun Q, Korsmeyer S, Packer M, May HI, Hill JA, Virgin HW, Gilpin C, Xiao G, Bassel-Duby R, Scherer PE, Levine B, Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis, Nature, 481, 7382, 511–5, January 2012, 22258505, 3518436, 10.1038/nature10758, etal, JOURNAL, Nair U, Klionsky DJ, Activation of autophagy is required for muscle homeostasis during physical exercise, Autophagy, 7, 12, 1405–6, December 2011, 22082869, 3288013, 10.4161/auto.7.12.18315, Autophagy at the molecular level is only partially understood. A study of mice shows that autophagy is important for the ever-changing demands of their nutritional and energy needs, particularly through the metabolic pathways of protein catabolism. In a 2012 study conducted by the University of Texas Southwestern Medical Center in Dallas, mutant mice (with a knock-in mutation of BCL2 phosphorylation sites to produce progeny that showed normal levels of basal autophagy yet were deficient in stress-induced autophagy) were tested to challenge this theory. Results showed that when compared to a control group, these mice illustrated a decrease in endurance and an altered glucose metabolism during acute exercise.
Another study demonstrated that skeletal muscle fibres of collagen VI knockout mice showed signs of degeneration due to an insufficiency of autophagy which led to an accumulation of damaged mitochondria and excessive cell death.JOURNAL, Grumati P, Coletto L, Schiavinato A, Castagnaro S, Bertaggia E, Sandri M, Bonaldo P, Physical exercise stimulates autophagy in normal skeletal muscles but is detrimental for collagen VI-deficient muscles, Autophagy, 7, 12, 1415–23, December 2011, 22024752, 3288016, 10.4161/auto.7.12.17877, Exercise-induced autophagy was unsuccessful however; but when autophagy was induced artificially post-exercise, the accumulation of damaged organelles in collagen VI deficient muscle fibres was prevented and cellular homeostasis was maintained. Both studies demonstrate that autophagy induction may contribute to the beneficial metabolic effects of exercise and that it is essential in the maintaining of muscle homeostasis during exercise, particularly in collagen VI fibres.Work at the Institute for Cell Biology, University of Bonn, showed that a certain type of autophagy, i.e. chaperone-assisted selective autophagy (CASA), is induced in contracting muscles and is required for maintaining the muscle sarcomere under mechanical tension.JOURNAL, Arndt V, Dick N, Tawo R, Dreiseidler M, Wenzel D, Hesse M, Fürst DO, Saftig P, Saint R, Fleischmann BK, Hoch M, Höhfeld J, Chaperone-assisted selective autophagy is essential for muscle maintenance, Current Biology, 20, 2, 143–8, January 2010, 20060297, 10.1016/j.cub.2009.11.022, The CASA chaperone complex recognizes mechanically damaged cytoskeleton components and directs these components through a ubiquitin-dependent autophagic sorting pathway to lysosomes for disposal. This is necessary for maintaining muscle activity.JOURNAL, Ulbricht A, Eppler FJ, Tapia VE, van der Ven PF, Hampe N, Hersch N, Vakeel P, Stadel D, Haas A, Saftig P, Behrends C, Fürst DO, Volkmer R, Hoffmann B, Kolanus W, Höhfeld J, Cellular mechanotransduction relies on tension-induced and chaperone-assisted autophagy, Current Biology, 23, 5, 430–5, March 2013, 23434281, 10.1016/j.cub.2013.01.064,

Osteoarthritis

Because autophagy decreases with age and age is a major risk factor for osteoarthritis, the role of autophagy in the development of this disease is suggested. Proteins involved in autophagy are reduced with age in both human and mouse articular cartilage.JOURNAL, Caramés B, Taniguchi N, Otsuki S, Blanco FJ, Lotz M, Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis, Arthritis and Rheumatism, 62, 3, 791–801, March 2010, 20187128, 2838960, 10.1002/art.27305, Mechanical injury to cartilage explants in culture also reduced autophagy proteins.JOURNAL, Caramés B, Taniguchi N, Seino D, Blanco FJ, D'Lima D, Lotz M, Mechanical injury suppresses autophagy regulators and pharmacologic activation of autophagy results in chondroprotection, Arthritis and Rheumatism, 64, 4, 1182–92, April 2012, 22034068, 3288456, 10.1002/art.33444, Autophagy is constantly activated in normal cartilage but it is compromised with age and precedes cartilage cell death and structural damage.JOURNAL, Caramés B, Olmer M, Kiosses WB, Lotz MK, The relationship of autophagy defects to cartilage damage during joint aging in a mouse model, Arthritis & Rheumatology, 67, 6, 1568–76, June 2015, 25708836, 4446178, 10.1002/art.39073, Thus autophagy is involved in a normal protective process (chondroprotection) in the joint.

Cancer

Oftentimes, cancer occurs when several different pathways that regulate cell differentiation are disturbed. Autophagy plays an important role in cancer – both in protecting against cancer as well as potentially contributing to the growth of cancer.Furuya, N., Liang, X.H., and Levin, B. 2004. Autophagy and cancer. In Autophagy. D.J. Klionsky editor. Landes Bioscience. Georgetown, Texas, USA. 244-253. Autophagy can contribute to cancer by promoting survival of tumor cells that have been starved, or that degrade apoptotic mediators through autophagy: in such cases, use of inhibitors of the late stages of autophagy (such as chloroquine), on the cells that use autophagy to survive, increases the number of cancer cells killed by antineoplastic drugs.JOURNAL, Vlahopoulos S, Critselis E, Voutsas IF, Perez SA, Moschovi M, Baxevanis CN, Chrousos GP, New use for old drugs? Prospective targets of chloroquines in cancer therapy, Current Drug Targets, 15, 9, 843–51, 2014, 25023646, 10.2174/1389450115666140714121514, The role of autophagy in cancer is one that has been highly researched and reviewed. There is evidence that emphasizes the role of autophagy both as a tumor suppressor as well as a factor in tumor cell survival. However, recent research has been able to show that autophagy is more likely to be used as a tumor suppressor according to several models.

Tumor suppressor

Several experiments have been done with mice and varying Beclin1, a protein that regulates autophagy. When the Beclin1 gene was altered to be heterozygous (Beclin 1+/-), the mice were found to be tumor prone.JOURNAL, Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, Rosen J, Eskelinen EL, Mizushima N, Ohsumi Y, Cattoretti G, Levine B, Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene, The Journal of Clinical Investigation, 112, 12, 1809–20, December 2003, 14638851, 297002, 10.1172/JCI20039, etal, However, when Beclin1 was overexpressed, tumor development was inhibited.JOURNAL, Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B, Induction of autophagy and inhibition of tumorigenesis by beclin 1, Nature, 402, 6762, 672–6, December 1999, 10604474, 10.1038/45257, etal, Care should be exercised when interpreting phenotypes of beclin mutants and attributing the observations to a defect in autophagy, however: Beclin1 is generally required for phosphatidylinositol 3- phosphate production and as such it affects numerous lysosomal and endosomal functions, including endocytosis and endocytic degradation of activated growth factor receptors. In support of the possibility that Beclin1 affects cancer development through an autophagy-independent pathway is the fact that core autophagy factors which are not known to affect other cellular processes and are definitely not known to affect cell proliferation and cell death, such as Atg7 or Atg5, show a much different phenotype when the respective gene is knocked out, which does not include tumor formation. In addition, full knockout of Beclin1 is embryonic lethal whereas knockout of Atg7 or Atg5 is not.Necrosis and chronic inflammation also has been shown to be limited through autophagy which helps protect against the formation of tumor cells.JOURNAL, Duran A, Linares JF, Galvez AS, Wikenheiser K, Flores JM, Diaz-Meco MT, Moscat J, The signaling adaptor p62 is an important NF-kappaB mediator in tumorigenesis, Cancer Cell, 13, 4, 343–54, April 2008, 18394557, 10.1016/j.ccr.2008.02.001, etal,

Tumor cell survival

Alternatively, autophagy has also been shown to play a large role in tumor cell survival. In cancerous cells, autophagy is used as a way to deal with stress on the cell.JOURNAL, Paglin S, Hollister T, Delohery T, Hackett N, McMahill M, Sphicas E, Domingo D, Yahalom J, A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles, Cancer Research, 61, 2, 439–44, January 2001, 11212227, Induction of autophagy by miRNA-4673, for example, is a pro-survival mechanism that improves the resistance of cancer cells to radiation.JOURNAL, Dökümcü K, Simonian M, Farahani RM, miR4673 improves fitness profile of neoplastic cells by induction of autophagy, Cell Death & Disease, 9, 11, 1068, October 2018, 30341280, 6195512, 10.1038/s41419-018-1088-6, Once these autophagy related genes were inhibited, cell death was potentiated.JOURNAL, Jin S, White E, Role of autophagy in cancer: management of metabolic stress, Autophagy, 3, 1, 28–31, 2007, 16969128, 2770734, 10.4161/auto.3269, The increase in metabolic energy is offset by autophagy functions. These metabolic stresses include hypoxia, nutrient deprivation, and an increase in proliferation. These stresses activate autophagy in order to recycle ATP and maintain survival of the cancerous cells.JOURNAL, Yang ZJ, Chee CE, Huang S, Sinicrope FA, The role of autophagy in cancer: therapeutic implications, Molecular Cancer Therapeutics, 10, 9, 1533–41, September 2011, 21878654, 10.1158/1535-7163.MCT-11-0047, 3170456, Autophagy has been shown to enable continued growth of tumor cells by maintaining cellular energy production. By inhibiting autophagy genes in these tumors cells, regression of the tumor and extended survival of the organs affected by the tumors were found. Furthermore, inhibition of autophagy has also been shown to enhance the effectiveness of anticancer therapies.

Mechanism of cell death

Cells that undergo an extreme amount of stress experience cell death either through apoptosis or necrosis. Prolonged autophagy activation leads to a high turnover rate of proteins and organelles. A high rate above the survival threshold may kill cancer cells with a high apoptotic threshold.JOURNAL, Tavassoly I, Parmar J, Shajahan-Haq AN, Clarke R, Baumann WT, Tyson JJ, Dynamic Modeling of the Interaction Between Autophagy and Apoptosis in Mammalian Cells, Cpt, 4, 4, 263–72, April 2015, 26225250, 4429580, 10.1002/psp4.29, This technique can be utilized as a therapeutic cancer treatment.

Therapeutic target

New developments in research have found that targeted autophagy may be a viable therapeutic solution in fighting cancer. As discussed above, autophagy plays both a role in tumor suppression and tumor cell survival. Thus, the qualities of autophagy can be used as a strategy for cancer prevention. The first strategy is to induce autophagy and enhance its tumor suppression attributes. The second strategy is to inhibit autophagy and thus induce apoptosis.The first strategy has been tested by looking at dose-response anti-tumor effects during autophagy-induced therapies. These therapies have shown that autophagy increases in a dose-dependent manner. This is directly related to the growth of cancer cells in a dose-dependent manner as well. This data supports the development of therapies that will encourage autophagy. Secondly, inhibiting the protein pathways directly known to induce autophagy may also serve as an anticancer therapy.The second strategy is based on the idea that autophagy is a protein degradation system used to maintain homeostasis and the findings that inhibition of autophagy often leads to apoptosis. Inhibition of autophagy is riskier as it may lead to cell survival instead of the desired cell death.

Negative regulators of autophagy

Negative regulators of autophagy, such as mTOR, cFLIP, and EGFR are orchestrated to function within different stages of the autophagy cascade. The end-products of autophagic digestion may also serve as a negative- feedback regulatory mechanism to stop prolonged activity.JOURNAL, Razaghi A, Heimann K, Schaeffer PM, Gibson SB, Negative regulators of cell death pathways in cancer: perspective on biomarkers and targeted therapies, Apoptosis, 23, 2, 93–112, February 2018, 29322476, 10.1007/s10495-018-1440-4,

Parkinson disease

Parkinson disease is a neurodegenerative disorder partially caused by the cell death of brain and brain stem cells in many nuclei like the substantia nigra. Parkinson's disease is characterized by inclusions of a protein called alpha-synuclien (Lewy bodies) in affected neurons that cells cannot break down. Deregulation of the autophagy pathway and mutation of alleles regulating autophagy are believed to cause neurodegenerative diseases.{{Citation needed|date=December 2018}} Autophagy is essential for neuronal survival.{{Citation needed|date=December 2018}} Without efficient autophagy, neurons gather ubiquitinated protein aggregates and degrade.{{Citation needed|date=December 2018}} Ubiquitinated proteins are proteins that have been tagged with ubiquitin to get degraded. Mutations of synuclien alleles lead to lysosome pH increase and hydrolase inhibition. As a result, lysosomes degradative capacity is decreased. There are several genetic mutations implicated in the disease, including loss of function PINK1JOURNAL, Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, González-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW, Hereditary early-onset Parkinson's disease caused by mutations in PINK1, Science, 304, 5674, 1158–60, May 2004, 15087508, 10.1126/science.1096284, and Parkin.JOURNAL, Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N, Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism, Nature, 392, 6676, 605–8, April 1998, 9560156, 10.1038/33416, Loss of function in these genes can lead to damaged mitochondrial accumulation and protein aggregates than can lead to cellular degeneration. Mitochondria is involved in Parkinson's disease. In idiopathic Parkinson's disease, the disease is commonly caused by dysfunctional mitochondria, cellular oxidative stress, autophagic alterations and the aggregation of proteins. These can lead to mitochondrial swelling and depolarization.JOURNAL, Esteves AR, Arduíno DM, Silva DF, Oliveira CR, Cardoso SM, Mitochondrial Dysfunction: The Road to Alpha-Synuclein Oligomerization in PD, Parkinson's Disease, 2011, 693761, January 2011, 21318163, 3026982, 10.4061/2011/693761,

Significance of autophagy as a drug target

Since dysregulation of autophagy is involved in the pathogenesis of a broad range of diseases, great efforts are invested to identify and characterize small synthetic or natural molecules that can regulate it.Moosavi MA, Haghi A, Rahmati M, Taniguchi H, Mocan A, Echeverría J, Gupta VK, Tzvetkov NT, Atanasov AG. Phytochemicals as potent modulators of autophagy for cancer therapy. Cancer Lett. 2018 Jun 28;424:46-69. doi: 10.1016/j.canlet.2018.02.030.

See also

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References

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Further reading

External links

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