Autophagy - Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Autophagy

Autophagy
From Wikipedia, the free encyclopedia

Autophagy (or autophagocytosis) is the basic catabolic mechanism that involves cell degradation of unnecessary or dysfunctional cellular components [1] (from the Greek through the lysosomal machinery words, auto "self" and phagein "to eat"). The breakdown of cellular components can ensure cellular survival during starvation by maintaining cellular energy [1] Autophagy, if regulated, ensures the synthesis, levels. [1] degradation and recycling of cellular components. During this process, targeted cytoplasmic constituents are isolated from the rest of the cell within the autophagosomes, which are then fused with lysosomes [2] There are three dierent and degraded or recycled. forms of autophagy that are commonly described, which include macroautophagy, microautophagy and [3] In the context of chaperone-mediated autophagy. disease, autophagy has been seen as an adaptive response to survival, whereas in other cases it appears [2] to promote cell death and morbidity.

Contents
1 Process and Pathways 2 Functions 2.1 Nutrient starvation 2.2 Infection 2.3 Repair mechanism 2.4 Programmed cell death 3 Autophagy and caloric restriction 4 Autophagy and exercise 5 See also 6 References 7 External links 8 Further reading 9 External links

(A) Diagram of autophagy; (B) Electron micrograph of autophagic structures in the fatbody of a fruit y larva; (C) Fluorescently labeled autophagosomes in liver cells of starved mice.

Process and Pathways

There are three main pathways involved in autophagy and these are mediated by the [4][5] autophagy-related genes and their associated proteases.

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Macroautophagy is the main pathway, occurring mainly to eradicate damaged cell [6] This involves the formation of a double membrane organelles or unused proteins. [5][7] This formation is induced by around the organelle known as an autophagosome. class 3 phosphoinositide-3-kinase, the autophagy-related gene (Atg) 6 (also known as [8] Other proteases such as Atg4, Atg12, Atg5, and Beclin-1) and ubiquitin complexes. Atg16 are also involved in the regulation of these pathways. The autophagosome travels through the cytoplasm of the cell to a lysosome, and the two membranes fuse together [5] Within the lysosome, the allowing the autophagosome to enter via endocytosis. [9] contents of the autophagosome are degraded via acidic lysosomal hydrolases. Microautophagy, on the other hand, involves the direct engulfment of cytoplasmic [10] This occurs by invagination, meaning the inward folding material into the lysosome. [7] of the lysosomal membrane, or cellular protrusion. Chaperone-mediated autophagy, or CMA, is a very complex and specic pathway, [7][11] This means that which involves the recognition by the hsc70-containing complex. a protein must contain the recognition site for this hsc70 complex which will allow it to [9] This bind to this chaperone, forming the CMA- substrate/chaperone complex. complex then moves to the lysosomal membrane-bound protein that will recognise and [12] Upon recognition, the bind with the CMA receptor, allowing it to enter the cell. substrate protein gets unfolded and it is translocated across the lysosome membrane [4][5][12] CMA is signicantly with the assistance of the lysosomal hsc70 chaperone. dierent 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 [12][6] lysosomal barrier.

Functions
Nutrient starvation
Autophagy has important roles in various cellular functions, one particular example is in yeasts, where the nutrient starvation induces a high level of autophagy, which allows unneeded proteins to be degraded and the amino acids recycled for the synthesis of [13][14][15] In higher eukaryotes, autophagy is proteins that are essential for survival. also induced in response to the nutrient depletion that occurs in animals at birth after severing of the trans-placental food supply, as well as that of nutrient starved cultured [16][17] Mutant yeast cells that have a reduced autophagic capability cells and tissues. [18] Studies on the apg mutants suggest rapidly perish in nutrition-decient conditions. 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.[18] A gene known as Atg7 has been implicated in nutrient-mediated autophagy, as mice studies have shown that starvation-induced autophagy was impaired [17] in Atg7-decient mice.

Infection

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Autophagy has been recognized as an immune mechanism. It plays a role in the destruction of intracellular pathogens, in a process of degradation of dysfunctional intracellular organelles. Intracellular pathogens such as Mycobacterium tuberculosis is the bacterium which is responsible for tuberculosis and it can survive within the cells by blocking the maturation of its phagosome into a degradative organelle called a [19] Stimulation of autophagy in infected cells helps overcome the block phagolysosome. and aids the cell to get rid of the pathogens. The virus (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 member of the PRRs 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, among other anti-viral cytokines. A subset of viruses and bacteria subvert the autophagic [20] Galectin-8 has recently been identied as pathway to promote their own replication. an intracellular "danger receptor", able to initiate autophagy against intracellular pathogens. When galectin-8 binds to a damaged vacuole, it recruits autophagy adaptor such as NDP52 leading to the formation of an autophagosome and bacterial [21] degradation.

Repair mechanism
Autophagy degrades damaged organelles, cell membranes and proteins, and the failure of autophagy is thought to be one of the main reasons for the accumulation of cell [22] damage and aging.

Programmed cell death

Apoptosis (cell suicide) is not the only form of programmed cell death (PCD). [23] Recent studies have provided evidence that there is another mechanism of PCD which 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 [23] This hypothesis as well as previous morphologically dened as autophagic PCD. reports that cells with autophagic features often exist in regions where PCD is occurring seem to support the existence of 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 cannot 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 [23] Studies of the metamorphosis of insects might actually be a survival mechanism. have shown cells undergoing a form of PCD that appears distinct from other forms; [24] these have been proposed as examples of autophagic cell death.

Autophagy and caloric restriction

Research suggests that autophagy is required for the lifespan-prolonging eects of [25] A 2010 French study of nematodes, mice and ies showed that caloric restriction. inhibition of autophagy exposed cells to metabolic stress. Resveratrol and the dietary restriction prolonged the lifespan of normal, autophagy-procient nematodes, but not of
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nematodes in which autophagy had been inhibited by knocking out Beclin 1 (a known [25] Research is ongoing in this eld. autophagic modulator).

Autophagy and exercise

Autophagy is essential for basal homeostasis however; it is also extremely important in [26][27] Although the maintaining muscle homeostasis during physical exercise. molecular level of this research is only partially understood, it is understood in the study of mice that autophagy is important for the ever changing demands in nutritional and energy needs of exercise, particularly through the metabolic pathways of protein [26][27] In a 2012 study conducted by the Tokyo Medical University in Japan, catabolism. mutant mice with a knock-in mutation of BCL2 phosphorylation sites to produce progeny that showed normal levels of basal autophagy yet were decient in stress[26] Results showed that when induced autophagy were tested to challenge this theory. compared to a control group (physiologically normal/unchanged), these mice illustrated [26] a decrease in endurance and altered glucose metabolism during acute exercise. Another study demonstrated that skeletal muscle bres of collagen VI in mice showed signs of degeneration due to an insuciency of autophagy and this lead to an [28] Exercise induced accumulation of damaged mitochondria and excessive apoptosis. autophagy is unsuccessful however; when autophagy was induced post-exercise articially, the accumulation of damaged organelles in collagen VI bres was prevented [28] Both studies demonstrate that autophagy and cellular homeostasis was maintained. induction may contribute to the benecial metabolic eects of exercise and that it is essential in the maintaining muscle homeostasis during exercise, particularly in [26][27][28] collagen VI bres.

See also
Autophagy database Autophagin Apoptosis Residual body Sub-lethal damage Ubiquitin Xenophagy

References
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External links
Autophagy journal homepage (http://www.landesbioscience.com/journals /autophagy/)

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Further reading
Liu, Y.; Bassham, D. C. (2012). "Autophagy: Pathways for Self-Eating in Plant Cells". Annual Review of Plant Biology 63: 215237. doi:10.1146/annurev-arplant042811-105441 (http://dx.doi.org/10.1146%2Fannurev-arplant-042811-105441) . PMID 22242963 (//www.ncbi.nlm.nih.gov/pubmed/22242963) .

External links
Autophagy, a journal produced by Landes Bioscience and edited by DJ Klionsky (http://www.landesbioscience.com/journals/autophagy/) LongevityMeme entry describing PubMed article on the eects of autophagy and lifespan (http://www.longevitymeme.org/news/view_news_item.cfm?news_id=2668) Autophagolysosome on Drugs.com (http://www.drugs.com /dict/autophagolysosome.html) HADb, a Human Autophagy dedicated Database (http://www.autophagy.lu/) Autophagy DB, an autophagy database that covers all eukaryotes (http://tpapg.genes.nig.ac.jp/autophagy/) Self-Destructive Behavior in Cells May Hold Key to a Longer Life (http://www.nytimes.com/2009/10/06/science/06cell.html) Exercise as Housecleaning for the Body (http://well.blogs.nytimes.com/2012/02 /01/exercise-as-housecleaning-for-the-body) Retrieved from "http://en.wikipedia.org/w/index.php?title=Autophagy& oldid=528457122" Categories: Cellular processes Programmed cell death Immunology

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