The term Autophagy, originated from Greek defined as self-eating, as basic catabolic mechanism of cell, is an intracellular degradation process by selective and nonselective manners, in which cytoplasmic dysfunctional components including damaged organelles, defected proteins and invasive microbes are degraded and recycled through lysosome in mammalian or in form of vacuole in yeast. Following degradation process, the breakdown products are released back into the cytoplasm in order to recycle the macromolecular constituents and keep cell viability during stress conditions e.g. nutrient starvation by maintaining cellular energy levels. During this process, targeted cytoplasmic components are sequestered from the rest of the cell within a cup-shaped double-membraned vesicle known as an autophagosome. The outer layer of autophagosome then fuses with a lysosome and its cargo is degraded by lysosomal enzymes.
Two key protein degradation and recycling pathways are defined in eukaryotic cells; the UPS (ubiquitin-proteosome system) and the autophagy –lysosome pathways. The UPS regulates levels of short-live proteins whereas autophagy is responsible for the degradation of long lived proteins and organelles. Up to present time, there three main types of autophagy accepted in underlying-related mechanisms that are described as following: macroautophagy, microautophagy and chaperone-mediated autophagy. Macroautophagy (usually referred to autophagy) is characterized by double membrane vesicle around cytoplasmic cargos resulting in autophagosome formation which is induced by class 3 phosphoinositide-3-kinase (PI3K), Beclin-1 (also known Atg6) and ubiquitin-like conjugation reactions. Other autophagy-related proteins such as Atg4, Atg5, Atg12, and Atg16 are also involved in the regulation of autophagosome formation. In contrast to other types, macroautophagy allows the delivery of bulk of different cargo molecules into the lysosome to degrade by lysosomal acidic enzymes.
Microautophagy (lesser known self-eating) is the randomly engulfment of cytoplasmic materials and translocates them into the lysosome/vacuole for further degradation by either direct invagination, protrusion of the lysosomal or vacuolar membrane. The only cellular function that has been assigned to microautophagy is the turnover of peroxisomes under specific conditions in fungi.
Chaperone-mediated autophagy (CMA) is a very complex and specific process which has been characterized in higher eukaryotes but not usual in yeast. CMA targets only single proteins and a chaperone protein (heat shock protein; hsc70) binds to its cytosolic targets and unfolding of the protein eventually occurs which resulted in the CMA/chaperone complex forming. Further, the unfolded cytosolic target protein is subsequently translocated directly into the lysosome for its degradation.
Photo credit: Clin Sci (Lond). 2009 May; 116(9):697-712. doi: 10.1042/CS20080508.
In addition, autophagy plays a key role in adaptive responses in different forms cellular insults including stress, homeostasis, cellular differentiation and development. Under normal conditions, this process occurs at low levels to achieve housekeeping functions such as degradation of defected proteins or dysfunctional organelles. Moreover, in the presence of stress conditions e.g. starvation, oxidative stress, hormonal imbalance or removal of protein aggregated (as internal needs); the process of autophagy is up-regulated. In contrary, autophagy may also have essential role in stress-induced cell death. With regarding to critical role of autophagy pharmacological approaches represent a major challenge for clinicians to treat diseases in human pathology such as cardiovascular diseases, neurodegenerative disorders, nephropathies, cancers, and aging.
By: Dr. A. Rezabakhsh