The process through which dysfunctional cellular components undergo degradation within the cell via the action of lysosomes is known as autophagy. Cytoplasm components are reduced to basic components and then restored to the cytosol for reuse.
Being a dynamic process, autophagy is present in all cells at low basal levels, but it can also be upregulated by hypoxia, nutrient starvation, or other stimuli. This process is also a strictly regulated pathway which has a critical housekeeping role at basal level enabling cells to survive in response to numerous stress conditions. (Mizushima et al., 2010).
Types of autophagy
At present, mammalian cells have three types of autophagy as demonstrated by Glick and colleagues (Glick et al., 2010):
In macroautophagy, which is the primary autophagic pathway, cytoplasmic cargo is delivered to the lysosome via an intermediary double membrane-bound vesicle called an autophagosome; this vesicle binds with the lysosome to form an autolysosome.
In microautophagy – another autophagic pathway – cytoplasmic cargo is directly engulfed into the lysosome via invagination of the lysosomal membrane. This pathway is essential in maintaining cell survival, membrane homeostats, and organellar size under nitrogen restriction (Li et al., 2012).
Chaperone-mediated autophagy (CMA)
In chaperone-mediated autophagy (CMA), cytoplasmic proteins are directly translocated across the lysosomal membrane in a complex along with chaperone proteins. The lysosomal membrane receptor LAMP-2A (lysosomal-associated membrane protein 2A) detects these chaperone proteins, leading to their unfolding and degradation.
Figure 1. Different stages of autophagic process with (a) uninduced cell followed by (b) induction of autophagy and phagophore formation, (c) autophagophore completion and (d) fusion with lysosomes.
Cellular and molecular mechanisms
In the autophagy process, double membrane vesicles are formed that enwrap parts of the cytoplasm. The following stages are involved in the process:
Induction and formation of phagophore
Phagophore is a unique flat membrane, whose formation encourages/ignites/activates autophagy in response to various stimuli. This initiation needs two protein complexes that play a role in the regulation of autophagosome formation. is encourage Two protein complexes are necessary in the regulation of autophagosome formation. The formation of a unique flat membrane (phagophore) encourages autophagy in reaction to various stimuli.
Elongation and formation of autophagosome
A double-membraned organelle called autophagosome is formed by the elongation of the phagophore. This stage is a straight forward sequestration, where degradation does not take place. Both the outer and inner surfaces of the autophagosome contain LC3B-II. During the autophagy process, there is increased synthesis and processing of LC3, which is used as a marker for monitoring autophagy levels in cells.
Fusion, degradation, and recycling
Fully formed autophagosome are bound to the lysosomes in the cell. The same machinery involved in the fusion of homotypic vacuole membrane also mediates the fusion of autophagosome and lysosome.
Vesicular cargo degradation depends on a set of lysosomal/vacuolar acid hydrolases. The small molecules produced from the degradation, especially amino acids, are sent back to the cytosol for maintenance of cellular functions and synthesis of proteins.
Autophagy in diseases
Several pathophysiological processes including neurodegenerative and metabolic disorders, cancer, and pulmonary and cardiovascular diseases are largely associated with autophagy. According to Choi et al., 2013. Autophagy also plays a critical role in exercise and aging.
The role of Beclin 1 (Liang et al., 1999) initially linked autophagy to cancer. As a crucial component of autophagy pathway, Beclin 1 has been mapped to tumor susceptibility and since then several tumor-suppressor proteins have been detected that play a role in the regulation of autophagy pathway (for example, PTEN, Bcl2, p53 etc).
The autophagic mechanism is exploited by the tumor cells, allowingthe tumor cells to defeat nutrient-limiting conditions and promote tumor growth. Research has demonstrated that the tumor microenvironment can be modulated by autophagy by through supplying nutrients, promoting angiogenesis, and modulating the inflammatory response (Yang et al., 2015).
These diseases are defined by the buildup of toxic or mutant proteins (Ravikumar et al., 2002; Ravikumar et al, 2004). Autophagic pathway has been shown to assist in cell survival by eliminating unnecessary protein aggregates and cellular organelle. Neurodegeneration occurs when autophagy specific genes in neural cells are disrupted (Komatsu et al., 2006; Hara et al., 2006).
Autophagic pathway is crucial for normal adaptation, repair, and maintenance of the heart tissue. It is therefore not surprising that autophagic deficiencies have been linked with various cardiac pathologies (Cuervo, 2004).
Autophagy is involved in the immune defense mechanism against the invading pathogens and bacteria. Following infection, processes like antigen presentation, inflammation, capture of microorganisms and degradation are regulated by autophagy (Levine et al., 2011).
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