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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 which plays a normal part in cell growth, development, and homeostasis, where it helps 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 sharing 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], however, many questions still remain to be elucidated about the actual processes and mechanisms involved. Its role in disease is not well categorised, it may help to halt the progression of some diseases and plays a protective role against infection by intracellular pathogens; however, in some situations it may actually contribute to the development of a disease.
Autophagy is derived from Greek roots: ''auto'' - self, and ''phagy'' - eating. It is sometimes thought of a synonym for self-cannibalismBenecke, Mark "First report of non-psychotic self-cannibalism (autophagy), tongue splicing and scar patterns (scarification) as an extreme form of cultural body modification in a Western civilization", however it is almost exclusively a term applied in cell biology to the process of controlled cellular degradation. While the use of Greek roots may be correct in using these two terms as synonyms, each is applied to different areas of study and should not be used interchangeably. One of the most exciting finds was a previously unknown gene common to type 1 diabetes and Crohn's disease, a type of inflammatory bowel disorder, suggesting that they share similar biological pathways. The team also unexpectedly found a process known as autophagy - a process of clearing bacteria from within cells - is important in the development of Crohn's disease
Autophagy can be broadly separated into two types: ''macroautophagy'' and ''microautophagy''. Macroautophagy involves the formation of a membrane containing target materials moving into the lysosome while microautophagy is the direct invagination of materials into the lysosome. Specific types of autophagy include:
★ 'Chaperone-mediated autophagy', a term used to describe the autophagocytosis of proteins marked with a specific peptide sequence. Chaperone molecules bind to and transport marked proteins to the lysosome for degradation.
★ '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.
'Macroautophagy' is the sequestration 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 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.[2]
'Microautophagy', on the other hand, happens when lysosomes directly engulf cytoplasm by invaginating, protrusion, and/or septation of the lysosomal limiting membrane.
Autophagy is part of everyday normal cell growth and development where mTOR plays an important regulatory role.
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[3]. Mutant yeast cells which have a reduced autophagic capability rapidly perish in nutrition-deficient conditions[4]. 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[5].
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[6].
It has been proposed that autophagy resulting in the total destruction of the cell is one of several types of programmed cell death, though no conclusive evidence exists for such a process[7]. 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 which appears distinct from other forms, these have been proposed as examples of autophagic cell death[8].
It is not known if autophagic activity in dying cells actually causes death or if it simply occurs as a process alongside it. In many neurological diseases, 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 if the increase in autophagosomes indicates an increase in autophagic activity or decreased autophagosome-lysosome fusion. Recently it has been argued that autophagy might actually be a survival mechanism on behalf of the cell.
★ Autophagy network
★ Autophagin
★ Apoptosis
★ Ubiquitin
★ ''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
1. Approaching the Molecular Mechanism of Autophagy, Stromhaug PE, Klionsky DJ, , , Traffic, 2001
2. Rubinsztein DC et al. (2005) Autophagy and Its Possible Roles in Nervous System Diseases, Damage and Repair. Autophagy 1(1):11-22. PMID 16874055
3. Autophagy: molecular machinery for self-eating, Yorimitsu T, Klionsky DJ, , , Cell Death and Differentiation (2005) 12, 1542–1552, 2005
4. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae., Tsukada M, Ohsumi Y, , , FEBS Lett., 1993
5. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice, M Komatsu ''et al.'', , , JCB, 2005
6. Autophagy Is a Defense Mechanism Inhibiting BCG and Mycobacterium tuberculosis Survival in Infected Macrophages, Gutierrez MG ''et al''., , , Cell, 2004
7. Another way to die: autophagic programmed cell death, Tsujimoto Y, Shimizu S, , , Cell Death and Differentiation, 2005
8. Do All Programmed Cell Deaths Occur Via Apoptosis?, Schwartz LM, ''et al'', , , Proceedings of the National Academy of Sciences, 1993
A variety of autophagic processes exist, all sharing 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], however, many questions still remain to be elucidated about the actual processes and mechanisms involved. Its role in disease is not well categorised, it may help to halt the progression of some diseases and plays a protective role against infection by intracellular pathogens; however, in some situations it may actually contribute to the development of a disease.
| Contents |
| Etymology |
| Types |
| Process |
| Functions |
| Nutrient starvation |
| Infection |
| Programmed cell death |
| See also |
| External links |
| References |
Etymology
Autophagy is derived from Greek roots: ''auto'' - self, and ''phagy'' - eating. It is sometimes thought of a synonym for self-cannibalismBenecke, Mark "First report of non-psychotic self-cannibalism (autophagy), tongue splicing and scar patterns (scarification) as an extreme form of cultural body modification in a Western civilization", however it is almost exclusively a term applied in cell biology to the process of controlled cellular degradation. While the use of Greek roots may be correct in using these two terms as synonyms, each is applied to different areas of study and should not be used interchangeably. One of the most exciting finds was a previously unknown gene common to type 1 diabetes and Crohn's disease, a type of inflammatory bowel disorder, suggesting that they share similar biological pathways. The team also unexpectedly found a process known as autophagy - a process of clearing bacteria from within cells - is important in the development of Crohn's disease
Types
Comparison of macroautophagy and microautophagy
Autophagy can be broadly separated into two types: ''macroautophagy'' and ''microautophagy''. Macroautophagy involves the formation of a membrane containing target materials moving into the lysosome while microautophagy is the direct invagination of materials into the lysosome. Specific types of autophagy include:
★ 'Chaperone-mediated autophagy', a term used to describe the autophagocytosis of proteins marked with a specific peptide sequence. Chaperone molecules bind to and transport marked proteins to the lysosome for degradation.
★ '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 sequestration 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 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.[2]
'Microautophagy', on the other hand, happens when lysosomes directly engulf cytoplasm by invaginating, protrusion, and/or septation of the lysosomal limiting membrane.
Autophagy is part of everyday normal cell growth and development where 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[3]. Mutant yeast cells which have a reduced autophagic capability rapidly perish in nutrition-deficient conditions[4]. 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[5].
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[6].
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, though no conclusive evidence exists for such a process[7]. 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 which appears distinct from other forms, these have been proposed as examples of autophagic cell death[8].
It is not known if autophagic activity in dying cells actually causes death or if it simply occurs as a process alongside it. In many neurological diseases, 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 if the increase in autophagosomes indicates an increase in autophagic activity or decreased autophagosome-lysosome fusion. Recently it has been argued that autophagy might actually be a survival mechanism on behalf of the cell.
See also
★ Autophagy network
★ Autophagin
★ Apoptosis
★ 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
1. Approaching the Molecular Mechanism of Autophagy, Stromhaug PE, Klionsky DJ, , , Traffic, 2001
2. Rubinsztein DC et al. (2005) Autophagy and Its Possible Roles in Nervous System Diseases, Damage and Repair. Autophagy 1(1):11-22. PMID 16874055
3. Autophagy: molecular machinery for self-eating, Yorimitsu T, Klionsky DJ, , , Cell Death and Differentiation (2005) 12, 1542–1552, 2005
4. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae., Tsukada M, Ohsumi Y, , , FEBS Lett., 1993
5. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice, M Komatsu ''et al.'', , , JCB, 2005
6. Autophagy Is a Defense Mechanism Inhibiting BCG and Mycobacterium tuberculosis Survival in Infected Macrophages, Gutierrez MG ''et al''., , , Cell, 2004
7. Another way to die: autophagic programmed cell death, Tsujimoto Y, Shimizu S, , , Cell Death and Differentiation, 2005
8. Do All Programmed Cell Deaths Occur Via Apoptosis?, Schwartz LM, ''et al'', , , Proceedings of the National Academy of Sciences, 1993
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