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 protein aggregates 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'. The phagophore membrane ends fuse, forming a specialised vesicle called an Autophagosome. 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, preventing damage to the cell and tissues by removing harmful molecules, stopping 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.
One of the key products of autophagy, amino acids, can be used for anabolic processes within the cell.
Autophagy is controlled by mTOR (Mechanistic target of rapamycin), a kinase coded for by the mTOR gene. When mTOR is active, autophagy is suppressed. However, mTOR can be suppressed by low amino acid concentrations, allowing autophagy to produce more amino acids.
Types of autophagy
Macroautophagy - This is 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”. This is a double membrane structure that elongates and encloses part of the cytoplasm, as well as the target organelles or proteins. The resulting specialised vesicle is termed an “autophagosome”. The autophagosome then migrates to a lysosome to which it fuses via the outer membrane. It is important to note the outer membrane stays intact thus keeping the contents and Hydrolases within the “autolysosome” for recycling.
Microautophagy - This process differs from macroautophagy as it is only concerned with the degradation and recycling of cytoplasm in the cell. It also uses a different 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, where it is unfolded and taken into the organelle for degradation.
Mitophagy - The selective degradation of mitochondria by autophagy. This is used by the cell in order to remove damaged mitochondria, or as a mechanism to regulate the number of mitochondria present in the cell. This process is essential during some developmental processes, such as the maturation of reticulocytes, as mature red blood cells do not contain any mitochondria; all the mitochondria present in the cell before differentiation must be removed.
Xenophagy- Is the removal of intracellular pathogens from the cytosol or in pathogen containing vacuoles. This process is ensential to antibacterial and antiviral defenses, as well as the immune response. Xenophagy has also been shown as a protective role of tumourigenesis. In a recent study in bacteria-associated cancer, of the gram-negative Helicobacter pylori.
Autophagy has been a remarkable discovery. Knowing about the process of cell recycling has opened several possible therapeutic opportunities that will definitely be a point of interest in research in the following years. Exploiting autophagy in humans can lead to delayed ageing and prevention of neurodegenerative and cancerous diseases. Further study will also educate us about how bacterial pathogens prevent autophagosomes from working effectively at the onset of a pathogenic invasion. This would lead to the understanding of countless bacterial diseases, and will hopefully provide an insight on how they can be cured. Therefore, the study on autophagic mechanisms needs to continue to have a better understanding of this remarkable process.
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- ↑ 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.
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- ↑ 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 and 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
- ↑ 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
- ↑ 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
- ↑ Youle RJ, Narendra DP. Mechanisms of mitophagy. Nature Reviews Molecular Cell Biology. 2010; 12:9-14
- ↑ Deas E, Wood NW, Plun-Favreau H. Mitophagy and Parkinson’s disease: The PINK1-parkin link. Biochimica et Biophysica Acta. 2011; 1813(4): 623-633 Available from: doi: 10.1016/j.bbamcr.2010.08.007