An Overview of Autophagy

Introduction

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):

Macroautophagy

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.

Microautophagy

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.

Cancer

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).

Neurodegenerative diseases

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).

Cardiovascular diseases

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).

Infectious disease

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).

References

  1. Choi AM, Ryter SW, Levine B. (2013). Autophagy in human health and disease. N. Engl. J. Med., 368(19), 1845-1846
  2. Cuervo AM (2004). Autophagy: in sickness and in health. Trends Cell Bio., 14(2), 70-77
  3. Glick D, Barth S, Macleod KF (2010). Autophagy: cellular and molecular mechanisms. J. Pathol., 221(1), 3-12
  4. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H, Mizushima N (2006). Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature, 441(7095), 885-889
  5. Komatsu M, Waguri S, CHiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, Tanaka K (2006). Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature, 441(7095), 880-884
  6. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B (1999). Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature, 402(6762), 672-676
  7. Levine B, Mizushima N, Virgin HW (2011). Autophagy in immunity and inflammation. Nature, 469(7330), 323-335
  8. Li WW, Li J, Bao JK (2012). Microautophagy: lesser-known self-eating. Cell Mol. Life Sci., 69(7), 1125-1136
  9. Mizushima N, Yoshimori T, Levine B (2010). Methods in mammalian autophagy research. Cell, 140(3), 313-326
  10. Ravikumar B, Duden R, Rubinsztein DC (2002). Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet., 11(9), 1107-1117
  11. Ravikumar B, Vacher C, Berger Z, Davies LE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O'Kane CJ, Rubinsztein DC (2004). Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet., 36(6), 585-595
  12. Yang X, Yu DD, Yan F, Jing YY, Han ZP, Sun K, Liang L, Hou J, Wei LX (2015).  The role of autophagy induced by tumor microenvironment in different cells and stages of cancer. Cell Biosci., 5(1)

About Abcam

Abcam is a global life sciences company providing highly validated antibodies and other binders and assays to the research and clinical communities to help advance the understanding of biology and causes of disease.

Abcam’s mission is to serve life scientists to help them achieve their mission faster by listening to their needs, continuously innovating and improving and by giving them the tools, data and experience they want. Abcam’s ambition is to become the most influential life science company for researchers worldwide.

Sponsored Content Policy: News-Medical.net publishes articles and related content that may be derived from sources where we have existing commercial relationships, provided such content adds value to the core editorial ethos of News-Medical.Net which is to educate and inform site visitors interested in medical research, science, medical devices and treatments.

Last updated: Jan 16, 2018 at 5:41 AM

Other White Papers by this Supplier