Friday 23 April 2004
Definition: Autophagy is the degradation of intracellular components in lysosomes.
Autophagy is a cellular degradation pathway for the clearance of damaged or superfluous proteins and organelles. The recycling of these intracellular constituents also serves as an alternative energy source during periods of metabolic stress to maintain homeostasis and viability.
To survive extreme environmental conditions, and in response to certain developmental and pathological situations, eukaryotic organisms employ the catabolic process of autophagy.
This degradative pathway allows cells to eliminate large portions of the cytoplasm, from aberrant protein aggregates to superfluous or damaged organelles and even entire organisms such as invading bacteria.
Structures targeted for destruction are sequestered into large double-membrane vesicles called autophagosomes and then delivered into the interior of the lysosome or vacuole, where they are consumed by resident hydrolases.
Autophagosome formation during selective autophagy is dependent upon the cargoes, and in all cases seems to involve expansion of the sequestering membrane.
Autophagy refers to lysosomal digestion of the cell’s own components. In this process, intracellular organelles and portions of cytosol are first sequestered from the cytoplasm in an autophagic vacuole formed from ribosome-free regions of the rough endoplasmic reticulum.
The vacuole fuses with lysosomes or Golgi elements to form an autophagolysosome (autophagosome). Autophagy is a common phenomenon involved in the removal of damaged organelles during cell injury and the cellular remodeling of differentiation, and it is particularly pronounced in cells undergoing atrophy induced by nutrient deprivation or hormonal involution.
The autophagic vacuoles are membrane-bound vacuoles within the cell that contain fragments of cell components (e.g., mitochondria, endoplasmic reticulum) that are destined for destruction and into which the lysosomes discharge their hydrolytic contents. The cellular components are then digested.
Some of the cell debris within the autophagic vacuole may resist digestion and persist as membrane-bound residual bodies that may remain in the cytoplasm. An example of such residual bodies is the lipofuscin granules (lipofuscin deposits). When present in sufficient amounts, they impart a brown discoloration to the tissue (brown atrophy).
Autophagy and apoptosis
The functional relationship between apoptosis (’self-killing’) and autophagy (’self-eating’) is complex in the sense that, under certain circumstances, autophagy constitutes a stress adaptation that avoids cell death (and suppresses apoptosis), whereas in other cellular settings, it constitutes an alternative cell-death pathway.
Autophagy and apoptosis may be triggered by common upstream signals, and sometimes this results in combined autophagy and apoptosis; in other instances, the cell switches between the two responses in a mutually exclusive manner.
On a molecular level, this means that the apoptotic and autophagic response machineries share common pathways that either link or polarize the cellular responses.
Canonical and non-canonical autophagy
The autophagosome is the central organelle in macroautophagy, a vacuolar lysosomal catabolic pathway that degrades cytoplasmic material to fuel starving cells and eliminates intracellular pathogens.
Macroautophagy has important physiological roles during development, ageing and the immune response, and its cytoprotective function is compromised in various diseases.
A set of autophagy-related (ATG) proteins is hierarchically recruited to the phagophore, the initial membrane template in the construction of the autophagosome.
Macroautophagy can also occur in the absence of some of these key autophagy proteins, through the unconventional biogenesis of canonical autophagosomes.
autophagy in cancer
Canonical and non-canonical autophagy: variations on a common theme of self-eating? Codogno P, Mehrpour M, Proikas-Cezanne T. Nat Rev Mol Cell Biol. 2011 Dec 14;13(1):7-12. PMID: #22166994#
Scherz-Shouval R, Elazar Z. ROS, mitochondria and the regulation of autophagy. Trends Cell Biol. 2007 Sep;17(9):422-7. PMID: #17804237#
Martinet W, Knaapen MW, Kockx MM, De Meyer GR. Autophagy in cardiovascular disease. Trends Mol Med. 2007 Oct 26; PMID: #18029229#
Mathew R, Karantza-Wadsworth V, White E. Role of autophagy in cancer. Nat Rev Cancer. 2007 Dec;7(12):961-7. PMID: #17972889#
Klionsky DJ. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol. 2007 Nov;8(11):931-7. PMID: #17712358#
Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol. 2007 Sep;8(9):741-52. PMID: #17717517#
Cuervo AM. Autophagy in neurons: it is not all about food. Trends Mol Med. 2006 Oct;12(10):461-4. PMID: #16931158#
Reggiori F, Klionsky DJ. Autophagosomes: biogenesis from scratch? Curr Opin Cell Biol. 2005 Aug;17(4):415-22. PMID: #15978794#
Kondo Y, Kanzawa T, Sawaya R, Kondo S. The role of autophagy in cancer development and response to therapy. Nat Rev Cancer. 2005 Sep;5(9):726-34. PMID: #16148885#
Kroemer G, Jaattela M. Lysosomes and autophagy in cell death control. Nat Rev Cancer. 2005 Nov;5(11):886-97. PMID: #16239905#
Levine B, Yuan J. Autophagy in cell death: an innocent convict? J Clin Invest. 2005 Oct;115(10):2679-88. PMID: #16200202#
Edinger AL, Thompson CB. Death by design: apoptosis, necrosis and autophagy. Curr Opin Cell Biol. 2004 Dec;16(6):663-9. PMID: #15530778#
Maria Cuervo A. Autophagy: in sickness and in health. Trends Cell Biol. 2004 Feb;14(2):70-7. PMID: #15102438#
Larsen KE, Sulzer D. Autophagy in neurons: a review. Histol Histopathol. 2002;17(3):897-908. PMID: #12168801#
Klionsky DJ, Emr SD: Autophagy as a regulated pathway of cellular degradation. Science 290:1717, 2000.
Dunn WA: Studies on the mechanisms of autophagy. J Cell Biol 110:1923, 1990.