Editing Autophagy (section)

==History==
Autophagy was first observed by [[Keith R. Porter]] and his student Thomas Ashford at the [[Rockefeller University|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 (biology)|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.<ref>{{cite journal | vauthors = Ashford TP, Porter KR | title = Cytoplasmic components in hepatic cell lysosomes | journal = The Journal of Cell Biology | volume = 12 | issue = 1 | pages = 198–202 | date = January 1962 | pmid = 13862833 | pmc = 2106008 | doi = 10.1083/jcb.12.1.198 }}</ref> 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.<ref>{{cite journal | vauthors = Hruban Z, Spargo B, Swift H, Wissler RW, Kleinfeld RG | title = Focal cytoplasmic degradation | journal = The American Journal of Pathology | volume = 42 | issue = 6 | pages = 657–83 | date = June 1963 | pmid = 13955261 | pmc = 1949709 }}</ref> 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.<ref>{{cite journal | vauthors = Deter RL, Baudhuin P, De Duve C | title = Participation of lysosomes in cellular autophagy induced in rat liver by glucagon | journal = The Journal of Cell Biology | volume = 35 | issue = 2 | pages = C11–6 | date = November 1967 | pmid = 6055998 | pmc = 2107130 | doi = 10.1083/jcb.35.2.c11 }}</ref><ref>{{cite journal | vauthors = Deter RL, De Duve C | title = Influence of glucagon, an inducer of cellular autophagy, on some physical properties of rat liver lysosomes | journal = The Journal of Cell Biology | volume = 33 | issue = 2 | pages = 437–49 | date = May 1967 | pmid = 4292315 | pmc = 2108350 | doi = 10.1083/jcb.33.2.437 }}</ref> This was the first time the fact that lysosomes are the sites of intracellular autophagy was established.<ref name="klionsky" /><ref>{{cite journal | vauthors = de Duve C | title = Lysosomes revisited | journal = European Journal of Biochemistry | volume = 137 | issue = 3 | pages = 391–7 | date = December 1983 | pmid = 6319122 | doi = 10.1111/j.1432-1033.1983.tb07841.x | doi-access = free }}</ref><ref>{{cite book | vauthors = Dunn WA, Schroder LA, Aris JP | chapter = Historical overview of autophagy | veditors = Wang HG |title= Autophagy and Cancer|year= 2013 | chapter-url= https://books.google.com/books?id=nXpDAAAAQBAJ |pages= 3–4 | publisher= Springer |isbn= 978-1-4614-6561-4 }}</ref>

In the 1990s several groups of scientists independently discovered autophagy-related genes using the [[Yeast|budding yeast]]. Notably, [[Yoshinori Ohsumi]] and Michael Thumm examined starvation-induced non-selective autophagy;<ref name="ohsumi 1992" /><ref name="thumm 1994" /><ref name="ohsumi 1993" /> in the meantime, [[Daniel J. Klionsky]] discovered the cytoplasm-to-vacuole targeting (CVT) pathway, which is a form of selective autophagy.<ref name="klionsky 1992" /><ref name="klionsky 1995" /> They soon found that they were in fact looking at essentially the same pathway, just from different angles.<ref name="klionksy 1996 jbc">{{cite journal | vauthors = Harding TM, Hefner-Gravink A, Thumm M, Klionsky DJ | title = Genetic and phenotypic overlap between autophagy and the cytoplasm to vacuole protein targeting pathway | journal = The Journal of Biological Chemistry | volume = 271 | issue = 30 | pages = 17621–4 | date = July 1996 | pmid = 8663607 | doi = 10.1074/jbc.271.30.17621 | doi-access = free }}</ref><ref name="klionsky 1996 pnas">{{cite journal | vauthors = Scott SV, Hefner-Gravink A, Morano KA, Noda T, Ohsumi Y, Klionsky DJ | title = Cytoplasm-to-vacuole targeting and autophagy employ the same machinery to deliver proteins to the yeast vacuole | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 22 | pages = 12304–8 | date = October 1996 | pmid = 8901576 | pmc = 37986 | doi = 10.1073/pnas.93.22.12304 | bibcode = 1996PNAS...9312304S | doi-access = free }}</ref> 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.<ref name="klionsky 2003 dc">{{cite journal | vauthors = Klionsky DJ, Cregg JM, Dunn WA, Emr SD, Sakai Y, Sandoval IV, Sibirny A, Subramani S, Thumm M, Veenhuis M, Ohsumi Y | title = A unified nomenclature for yeast autophagy-related genes | journal = Developmental Cell | volume = 5 | issue = 4 | pages = 539–45 | date = October 2003 | pmid = 14536056 | doi = 10.1016/s1534-5807(03)00296-x | url = https://www.rug.nl/research/portal/en/publications/a-unified-nomenclature-for-yeast-autophagyrelated-genes(221542fb-cff5-4604-a588-49ee7a7c84fb).html | hdl = 11370/221542fb-cff5-4604-a588-49ee7a7c84fb | s2cid = 39590247 | hdl-access = free }}</ref> The 2016 Nobel Prize in Physiology or Medicine was awarded to Yoshinori Ohsumi,<ref name=nobelprize /> although some have pointed out that if there is only one recipient of the award, it must be Ohsumi, but that the award could have been more inclusive.<ref name="nature news">{{cite journal | vauthors = Van Noorden R, Ledford H | title = Medicine Nobel for research on how cells 'eat themselves' | journal = Nature | volume = 538 | issue = 7623 | pages = 18–19 | date = October 2016 | pmid = 27708326 | doi = 10.1038/nature.2016.20721 | bibcode = 2016Natur.538...18V | doi-access = free }}</ref>

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.<ref name="levine 1999">{{cite journal | vauthors = Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B | title = Induction of autophagy and inhibition of tumorigenesis by beclin 1 | journal = Nature | volume = 402 | issue = 6762 | pages = 672–6 | date = December 1999 | pmid = 10604474 | doi = 10.1038/45257 | s2cid = 4423132 | bibcode = 1999Natur.402..672L }}</ref> 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.<ref name="gordon 2003">{{cite web|title=Autophagy in Stress, Development & Disease | date = 2003 | work = Gordon Research Conference |url=https://www.grc.org/programs.aspx?id=10449}}</ref> In 2005, Daniel J Klionsky launched [[Autophagy (journal)|''Autophagy'']], a scientific journal dedicated to this field. The first [[Keystone Symposia]] on autophagy was held in 2007 at Monterey.<ref name="keystone 2007">{{cite web |title=Autophagy in Health and Disease (Z3) |date=2007 |work= [[Keystone Symposia on Molecular and Cellular Biology]] |url=http://www.keystonesymposia.org/index.cfm?e=web.Meeting.Program&meetingid=838 |access-date=2016-10-04 |archive-date=2018-11-16 |archive-url=https://web.archive.org/web/20181116085631/http://www.keystonesymposia.org/index.cfm?e=web.Meeting.Program&meetingid=838 |url-status=dead }}</ref> 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 homocysteine methyltransferase (BHMT), a metabolic enzyme, could be used to assess autophagy flux in mammalian cells.
Macro, micro, and Chaperone mediated autophagy are mediated by autophagy-related genes and their associated enzymes.<ref name="mizushima 2011 ARCDB review" /><ref name="klionsky 2007 review" /><ref name=Lee12>{{cite journal | vauthors = Lee J, Giordano S, Zhang J | title = Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling | journal = The Biochemical Journal | volume = 441 | issue = 2 | pages = 523–40 | date = January 2012 | pmid = 22187934 | pmc = 3258656 | doi = 10.1042/BJ20111451 }}</ref><ref name=Yoshimori2002>{{cite journal | vauthors = Mizushima N, Ohsumi Y, Yoshimori T | title = Autophagosome formation in mammalian cells | journal = Cell Structure and Function | volume = 27 | issue = 6 | pages = 421–9 | date = December 2002 | pmid = 12576635 | doi = 10.1247/csf.27.421 | doi-access = free }}</ref><ref name="auto">{{cite journal | vauthors = Youle RJ, Narendra DP | title = Mechanisms of mitophagy | journal = Nature Reviews Molecular Cell Biology | volume = 12 | issue = 1 | pages = 9–14 | date = January 2011 | pmid = 21179058 | pmc = 4780047 | doi = 10.1038/nrm3028 }}</ref> Macroautophagy is then divided into bulk and selective autophagy. In the selective autophagy is the autophagy of organelles; mitophagy,<ref>{{cite journal | vauthors = Ding WX, Yin XM | title = Mitophagy: mechanisms, pathophysiological roles, and analysis | journal = Biological Chemistry | volume = 393 | issue = 7 | pages = 547–64 | date = July 2012 | pmid = 22944659 | pmc = 3630798 | doi = 10.1515/hsz-2012-0119 }}</ref> lipophagy,<ref name=":1" /> pexophagy,<ref>{{cite journal | vauthors = Till A, Lakhani R, Burnett SF, Subramani S | title = Pexophagy: the selective degradation of peroxisomes | journal = International Journal of Cell Biology | volume = 2012 | pages = 512721 | date = 2012 | pmid = 22536249 | pmc = 3320016 | doi = 10.1155/2012/512721 | doi-access = free }}</ref> chlorophagy,<ref>{{cite journal | vauthors = Lei L | title = Chlorophagy: Preventing sunburn | journal = Nature Plants | volume = 3 | issue = 3 | pages = 17026 | date = March 2017 | pmid = 28248315 | doi = 10.1038/nplants.2017.26 | s2cid = 30079770 | doi-access = free }}</ref> ribophagy<ref>{{cite journal | vauthors = An H, Harper JW | title = Systematic analysis of ribophagy in human cells reveals bystander flux during selective autophagy | journal = Nature Cell Biology | volume = 20 | issue = 2 | pages = 135–143 | date = February 2018 | pmid = 29230017 | pmc = 5786475 | doi = 10.1038/s41556-017-0007-x }}</ref> and others.

{{anchor|Macroautophagy}}'''Macroautophagy''' is the main pathway, used primarily to eradicate damaged cell [[organelle]]s or unused [[proteins]].<ref name=Levine11>{{cite journal | vauthors = Levine B, Mizushima N, Virgin HW | title = Autophagy in immunity and inflammation | journal = Nature | volume = 469 | issue = 7330 | pages = 323–35 | date = January 2011 | pmid = 21248839 | pmc = 3131688 | doi = 10.1038/nature09782 | bibcode = 2011Natur.469..323L }}</ref> First the phagophore engulfs the material that needs to be degraded, which forms a double [[Biological membrane|membrane]] known as an [[autophagosome]], around the organelle marked for destruction.<ref name=Yoshimori2002/><ref name=Pegan12>{{cite journal | vauthors = Česen MH, Pegan K, Spes A, Turk B | title = Lysosomal pathways to cell death and their therapeutic applications | journal = Experimental Cell Research | volume = 318 | issue = 11 | pages = 1245–51 | date = July 2012 | pmid = 22465226 | doi = 10.1016/j.yexcr.2012.03.005 }}{{Dead link|date=April 2020 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> The [[autophagosome]] then travels through the cytoplasm of the cell to a lysosome in mammals, or vacuoles in yeast and plants,<ref>{{cite journal | vauthors = Avin-Wittenberg T, Honig A, Galili G | title = Variations on a theme: plant autophagy in comparison to yeast and mammals | journal = Protoplasma | volume = 249 | issue = 2 | pages = 285–99 | date = April 2012 | pmid = 21660427 | doi = 10.1007/s00709-011-0296-z | s2cid = 17184033 }}</ref> and the two organelles fuse.<ref name=Yoshimori2002/> Within the lysosome/vacuole, the contents of the autophagosome are degraded via acidic lysosomal hydrolase.<ref name=Homma2011>{{Cite journal |archive-url=https://web.archive.org/web/20120801130843/http://tp-apg.genes.nig.ac.jp/autophagy/list/GeneList.html|archive-date=2012-08-01| url = http://tp-apg.genes.nig.ac.jp/autophagy/list/GeneList.html | year = 2011 | vauthors = Homma KS | title = List of autophagy-related proteins and 3D structures | journal = Autophagy Database | volume = 290 | access-date = 2012-10-08 }}</ref>

'''[[Microautophagy]]''', on the other hand, involves the direct engulfment of cytoplasmic material into the lysosome.<ref>{{Cite journal | title = The Discovery of Lysosomes and Autophagy | journal = Nature Education | page = 49 | volume = 3 |issue=9 | year = 2010 | vauthors = Castro-Obregon S |url = https://www.nature.com/scitable/topicpage/the-discovery-of-lysosomes-and-autophagy-14199828}}</ref> This occurs by invagination, meaning the inward folding of the lysosomal membrane, or cellular protrusion.<ref name=Pegan12/>

'''[[Chaperone-mediated autophagy]]''', or CMA, is a very complex and specific pathway, which involves the recognition by the hsc70-containing complex.<ref name=Pegan12/><ref name=Cuervo2008>{{cite journal | vauthors = Bandyopadhyay U, Kaushik S, Varticovski L, Cuervo AM | title = The chaperone-mediated autophagy receptor organizes in dynamic protein complexes at the lysosomal membrane | journal = Molecular and Cellular Biology | volume = 28 | issue = 18 | pages = 5747–63 | date = September 2008 | pmid = 18644871 | pmc = 2546938 | doi = 10.1128/MCB.02070-07 }}</ref> 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.<ref name="Homma2011" /> This complex then moves to the lysosomal membrane-bound protein that will recognise and bind with the CMA receptor. Upon recognition, the substrate protein gets unfolded and it is translocated across the lysosome membrane with the assistance of the lysosomal hsc70 chaperone.<ref name=Lee12/><ref name=Yoshimori2002/> 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.<ref name=Levine11/>

'''[[Mitophagy]]''' is the selective degradation of [[mitochondria]] by autophagy. It often occurs to defective mitochondria following damage or stress. Mitophagy promotes the turnover of mitochondria and prevents the accumulation of dysfunctional mitochondria which can lead to cellular degeneration. It is mediated by [[Atg32]] (in yeast) and [[Nix (gene)|NIX]] and its regulator [[BNIP3]] in mammals. Mitophagy is regulated by [[PINK1]] and [[parkin (ligase)|parkin]] proteins. The occurrence of mitophagy is not limited to the damaged mitochondria but also involves undamaged ones.<ref name="auto"/>

'''Lipophagy''' is the degradation of lipids by autophagy,<ref name=":1">{{cite journal | vauthors = Liu K, Czaja MJ | title = Regulation of lipid stores and metabolism by lipophagy | journal = Cell Death and Differentiation | volume = 20 | issue = 1 | pages = 3–11 | date = January 2013 | pmid = 22595754 | doi = 10.1038/cdd.2012.63 | pmc = 3524634 }}</ref> a function which has been shown to exist in both animal and fungal cells.<ref>{{cite journal | vauthors = Ward C, Martinez-Lopez N, Otten EG, Carroll B, Maetzel D, Singh R, Sarkar S, Korolchuk VI | title = Autophagy, lipophagy and lysosomal lipid storage disorders | journal = Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | volume = 1861 | issue = 4 | pages = 269–84 | date = April 2016 | pmid = 26778751 | doi = 10.1016/j.bbalip.2016.01.006 | doi-access = free | hdl = 1983/54269830-a38f-4546-93c2-424823701904 | hdl-access = free }}</ref> The role of lipophagy in plant cells, however, remains elusive.<ref>{{cite journal | vauthors = Elander PH, Minina EA, Bozhkov PV | title = Autophagy in turnover of lipid stores: trans-kingdom comparison | journal = Journal of Experimental Botany | volume = 69 | issue = 6 | pages = 1301–1311 | date = March 2018 | pmid = 29309625 | doi = 10.1093/jxb/erx433 | doi-access = free }}</ref> In lipophagy the target are lipid structures called [[lipid droplet]]s (LDs), spheric "organelles" with a core of mainly [[triacylglycerols]] (TAGs) and a unilayer of [[phospholipid]]s and [[membrane protein]]s. 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 cerevisiae]]''.<ref>{{cite journal | vauthors = van Zutphen T, Todde V, de Boer R, Kreim M, Hofbauer HF, Wolinski H, Veenhuis M, van der Klei IJ, Kohlwein SD | title = Lipid droplet autophagy in the yeast Saccharomyces cerevisiae | journal = Molecular Biology of the Cell | volume = 25 | issue = 2 | pages = 290–301 | date = January 2014 | pmid = 24258026 | pmc = 3890349 | doi = 10.1091/mbc.E13-08-0448 }}</ref> Lipophagy was first discovered in mice and published 2009.<ref>{{cite journal | vauthors = Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM, Czaja MJ | title = Autophagy regulates lipid metabolism | journal = Nature | volume = 458 | issue = 7242 | pages = 1131–5 | date = April 2009 | pmid = 19339967 | pmc = 2676208 | doi = 10.1038/nature07976 | bibcode = 2009Natur.458.1131S }}</ref>