Autophagy: an overview
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Autophagy is the process by which dysfunctional cellular components are degraded inside the cell through the action of lysosomes.
Components of the cytoplasm are broken down into basic components and returned to the cytosol for reuse. Autophagy is a dynamic process which is present in all cells at low levels under basal conditions, but stimuli such as nutrient starvation or hypoxia can lead to its upregulation.
Autophagy is a tightly regulated pathway which at basal level has an important housekeeping role allowing cells to survive in response to multiple stress conditions. (Mizushima et al., 2010).
Types of autophagy
There are currently three types of autophagy in mammalian cells as described by Glick and colleagues (Glick et al., 2010):
Macroautophagy
Macroautophagy is the main autophagic pathway and it is characterized by the delivery of cytoplasmic cargo to the lysosome through an intermediary double membrane-bound vesicle, known as an autophagosome, which fuses with the lysosome to form an autolysosome.
Microautophagy
Microautophagy involves the direct engulfment of cytoplasmic cargo into the lysosome through invagination of the lysosomal membrane. Microautophagy is important in the maintenance of organellar size, membrane homeostats and cell survival under nitrogen restriction (Li et al., 2012).
Chaperone-mediated autophagy (CMA)
Chaperone-mediated autophagy (CMA) involves the direct translocation of cytoplasmic proteins across the lysosomal membrane in a complex with chaperone proteins that are recognized by the lysosomal membrane receptor LAMP-2A (lysosomal-associated membrane protein 2A), resulting in their unfolding and degradation.
Cellular and Molecular Mechanisms
The process of autophagy involves formation of double membrane vesicles that enwrap portions of the cytoplasm. The process consist of following stages –
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.
Induction and phagophore formation
In response to various stimuli, autophagy is induced by formation of a unique flat membrane (phagophore). The initiation requires two protein complexes involved in the regulation of autophagosome formation.
Autophagosome elongation and formation
The elongation of the phagophore results in the formation of an autophagosome, which is typically a double-membraned organelle. This step is a simple sequestration, and no degradation occurs.
LC3B-II is found on both the inner and the outer surfaces of the autophagosome. During autophagy, the synthesis and processing of LC3 is increased and it is used as a marker to monitor levels of autophagy in cells.
Fusion, degradation and recycling
Completely formed autophagosome are fused with the lysosomes in the cell. Autophagosome-lysosome fusion is mediated by the same machinery that is involved in homotypic vacuole membrane fusion.
The degradation of the vesicular cargo is dependent on a series of lysosomal/vacuolar acid hydrolases. The resulting small molecules from the degradation, particularly amino acids, are transported back to the cytosol for protein synthesis and maintenance of cellular functions.
Autophagy in diseases
Autophagy has been widely implicated in many pathophysiological processes such as cancer, metabolic and neurodegenerative disorders as well as cardiovascular and pulmonary diseases. It also has an important role in aging and exercise (Choi et al., 2013).
Cancer
Autophagy was first linked to cancer through the role of Beclin 1 (Liang et al., 1999), which is essential for autophagy pathway, and has been mapped to tumor susceptibility. Since then, a number of tumor-suppressor proteins have been identified that are involved in control of autophagy pathway (e.g. p53, Bcl2, PTEN etc).
The tumor cells exploit the autophagic mechanism to provide a way for them to overcome nutrient-limiting conditions and facilitate tumor growth. Studies show that autophagy can modulate the tumor microenvironment by promoting angiogenesis, supply nutrients, and modulate inflammatory response (Yang et al., 2015).
Neurodegenerative diseases
Neurodegenerative diseases are characterized by accumulation of mutant or toxic proteins (Ravikumar et al., 2002; Ravikumar et al, 2004). It has been shown that autophagic pathway helps in cell survival by removing unwanted cellular organelle and protein aggregates. Disruption of autophagy specific genes in neural cells lead to neurodegeneration (Komatsu et al., 2006 ; Hara et al., 2006).
Cardiovascular diseases
Autophagic pathway is essential for normal maintenance, repair, and adaptation of the heart tissue. Unsurprisingly therefore, autophagic deficiencies have been associated with a variety of cardiac pathologies (Cuervo, 2004).
Infectious disease
Autophagy plays a key role in immune defence against invading bacteria and pathogens. Upon infection, autophagy regulates inflammation, antigen presentation and micro-organism capture and degradation (Levine et al., 2011).
References
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