Autophagy (cellular)

In cell biology, autophagy, or autophagocytosis, is a catabolic process involving the degradation of a cell's own components through the lysosomal machinery. It is a tightly-regulated process that plays a normal part in cell growth, development, and homeostasis, helping to maintain a balance between the synthesis, degradation, and subsequent recycling of cellular products. It is a major mechanism by which a starving cell reallocates nutrients from unnecessary processes to more-essential processes.

A variety of autophagic processes exist, all having in common the degradation of intracellular components via the lysosome. The most well-known mechanism of autophagy involves the formation of a membrane around a targeted region of the cell, separating the contents from the rest of the cytoplasm. The resultant vesicle then fuses with a lysosome and subsequently degrades the contents.

It was first described in the 1960s,^[1][2] but many questions about the actual processes and mechanisms involved still remain to be elucidated. Its role in disease is not well categorised; it may help to prevent or halt the progression of some diseases such as some types of neurodegeneration and cancer,^[3] and play a protective role against infection by intracellular pathogens; however, in some situations, it may actually contribute to the development of a disease.

Etymology

Autophagy is derived from Greek roots: auto, meaning 'self', and phagy, 'to eat'.

 Selective autophagy

• Pexophagy, autophagy selective for degradation of peroxisomes, which can be separated into macropexophagy and micropexophagy.
• Mitophagy, autophagy selective for degradation of mitochondria is called, which can be separated in macromitophagy and micromitophagy.
• Xenophagy, autophagy selective for degradation of intracellular bacteria and viruses.

 Process

Macroautophagy is the sequestrating of organelles and long-lived proteins in a double-membrane vesicle, called an autophagosome or autophagic vacuole (AV), inside the cell. Autophagosomes form from the elongation of small membrane structures known as autophagosome precursors. The formation of autophagosomes is initiated by class III phosphoinositide 3-kinase and autophagy-related gene (Atg) 6 (also known as Beclin-1). In addition, two further systems are involved, composed of the ubiquitin-like protein Atg8 (also known as light chain (LC)3) and the Atg4 protease on the one hand and the Atg12-Atg5-Atg16 complex on the other.^[4] The outer membrane of the autophagosome fuses in the cytoplasm with a lysosome to form an autolysosome or autophagolysosome where their contents are degraded via acidic lysosomal hydrolases.^[5]

Microautophagy, on the other hand, happens when lysosomes directly engulf cytoplasm by invaginating, protrusion, and/or septation of the lysosomal limiting membrane.

In Chaperone-mediated autophagy, or CMA, only those proteins that have a consensus peptide sequence get recognized by the binding of a hsc70-containing chaperone/co-chaperone complex. This CMA substrate/chaperone complex then moves to the lysosomes, where the CMA receptor lysosome-associated membrane protein type-2A (LAMP-2A) recognizes it; the protein is unfolded and translocated across the lysosome membrane assisted by the lysosomal hsc70 on the other side. CMA differs from macroautophagy and microautophagy in two main ways:

• The substrates are translocated across the lysosome membrane on a one-by-one basis, whereas in the macroautophagy and microautophagy the substrates are engulfed or sequestered in-bulk.
• CMA is very selective in what it degrades and can degrade only certain proteins and not organelles.

Autophagy is part of everyday normal cell growth and development wherein mTOR plays an important regulatory role.

 Functions

 Nutrient starvation

During nutrient starvation, increased levels of autophagy lead to the breakdown of non-vital components and the release of nutrients, ensuring that vital processes can continue.^[6] Mutant yeast cells that have a reduced autophagic capability rapidly perish in nutrition-deficient conditions.^[7] A gene known as Atg7 has been implicated in nutrient-mediated autophagy, as mice studies have shown that starvation-induced autophagy was impaired in Atg7-deficient mice.^[8]

 Infection

Autophagy plays a role in the destruction of some bacteria within the cell. Intracellular pathogens such as Mycobacterium tuberculosis persist within cells and block the normal actions taken by the cell to rid itself of it. Stimulating autophagy in infected cells overcomes the block and helps to rid the cell of pathogens.^[9]

 Programmed cell death

It has been proposed that autophagy resulting in the total destruction of the cell is one of several types of programmed cell death; yet, no conclusive evidence exists for such a process.^[10] Nevertheless, observations that cells possessing autophagic features in areas undergoing programmed cell death have led to the coining of the phrase autophagic cell death (also known as cytoplasmic cell death or type II cell death). Studies of the metamorphosis of insects have shown cells undergoing a form of programmed cell death that appears distinct from other forms, these have been proposed as examples of autophagic cell death.^[11]

It is not known whether autophagic activity in dying cells actually causes death or whether it simply occurs as a process alongside it. In many neurological diseases, in certain neuronal cell death pathways and after neuronal injury, there are increased numbers of autophagosomes. A causative relationship between autophagy and cell death has not been established. It is unclear whether the increase in autophagosomes indicates an increase in autophagic activity or decreased autophagosome-lysosome fusion.^[5] Recently it has been argued that autophagy might actually be a survival mechanism on behalf of the cell.^[10]

 See also

• Autophagy network
• Autophagin
• Apoptosis
• Sub-lethal damage
• Ubiquitin

 External links

• Autophagy, a journal produced by Landes Bioscience and edited by DJ Klionsky
• LongevityMeme entry describing PubMed article on the effects of autophagy and lifespan
• Autophagolysosome on Drugs.com

 References