Autophagy is an essential cellular process, used by cells to degrade damaged and unnecessary cytosolic macromolecules and organelles, for example, proteins. This prevents cell functions and pathways from being damaged or interrupted by aggregates of proteins or non-functioning organelles, a key cause of disease. Diseases associated with abnormal autophagy include Parkinson's Disease, osteoarthritis and cancer. Autophagy proceeds via a five-step mechanism that starts with the sequestration of cytosolic material by a double-membrane, known as a 'phagophore'. Once the phagophore membrane ends fuse to form a vesicle, the substrate has been fully sequestered. Once sequestration is complete, the autophagosome fuses with a lysosome and up to 40 hydrolytic enzymes digest the autophagosome's cargo.
Autophagy helps the cell maintain a stable internal environment and prevents damage occurring to the cell/ tissues by removing harmful molecules and preventing their accumulation. It is extremely prominent in the case of starving cells where nutrients are required to perpetuate cell survival, or when the cell experiences other stresses such as hypoxia or drug treatment.
There are a number of different autophagy mechanisms:
Macroautophagy - widely considered to be the most used pathway of autophagy in the body. It deals with the recycling of dysfunctional organelles and proteins which may have been damaged or incorrectly folded during their synthesis. The process starts with a piece of cellular machinery termed the isolation membrane or “phagophore” which is a double membrane structure that elongates and encloses part of the cytoplasm as well as the target organelles or proteins. This structure is termed an “autophagosome”. The autophagosome then migrates to a lysosome to which it fuses with via the outer membrane. It is important to note the outer membrane stays intact thus keeping the contents and hydrolyses within the “autolysosome” for recycling.
Microautophagy - This differs from macroautophagy as it is only concerned with the degradation and recycling of cytoplasm. It also differs in its mechanism. No autophagosome is formed as the lysosome itself directly degrades the cytoplasm by inward invaginations in its membrane.
Chaperone-mediated autophagy - only involves specific proteins within the cytoplasm. The target protein which is being degraded is recognised by a chaperone protein Hsc70 which binds to the target protein. This can then be recognised by specific receptors on the lysosomal membrane, unfolded and taken into the organelle for degradation.
Autophagy is controlled by mTOR (Mechanistic target of rapamycin), a kinase coded for by the MTOR gene. When mTOR is activated, autophagy is suppressed. mTOR can be suppressed by low amino acid concentrations, allowing autophagy to produce more amino acids.
- ↑ Klionsky, DJ. Autophagy revisited: A conversation with Christian de Duve. Autophagy. 2008;4(6):740-3. Available from: DOI: 10.4161/auto.6398.
- ↑ Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. The Journal of pathology. 2010;221(1):3-12. Available from: doi:10.1002/path.2697.
- ↑ Levine, B. Cell biology: Autophagy and cancer. Nature. 2007;446:745-747. Available from: doi:10.1038/446745a.
- ↑ Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Tokyo 102-0075, Japan
- ↑ Mizushima N. Autophagy: process and function. Genes &amp; Dev. 2007;21: 2861-2873. Available from: DOI:10.1101/gad.1599207.
- ↑ Yang Z J, Chee C E, Huang S, Sinicrope F A. The Role of Autophagy in Cancer: Therapeutic Implications. Molecular Cancer Therapeutics. 2011;10(9): 1533-1541. Available from: DOI: 10.1158/1535-7163.MCT-11-0047.
- ↑ Mizushima N, Komatsu M. Autophagy: Renovation of Cells and Tissues. Cell, 2011, Volume 147, Issue 4
- ↑ Li W, Li J, Bao J. Microautophagy: lesser-known self-eating. Cell and Molecular Life Science. 2012, Volume 69, 1125-1136.
- ↑ Kaushik S, Cuervo AM. Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends in Cell Biology. 2012, Volume 22 Issue 8, 407-417
- ↑ Lin S., Leng Z., Guo Y., Cai L., Cai Y., Li N., Shang H., Le W., Zhao W., Wu Z. (2015). Suppression of mTOR pathway and induction of autophagy-dependent cell death by cabergoline. Oncotarget, 5744 (Epub ahead of print)
- ↑ Carroll, B., Korolchuk, V., Sarkar, S. (2015). Amino acids and autophagy: cross-talk and co-operation to control cellular homeostasis. Amino Acids, 47(10), pp2065-2088