Autophagy

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Autophagy is an essential cellular process, used by [[Cell|cells]] to degrade damaged and unnecessary cytosolic macromolecules and organelles, for example, [[Proteins|proteins]]<ref>Klionsky, DJ. Autophagy revisited: A conversation with Christian de Duve. Autophagy. 2008;4(6):740-3. Available from: DOI: 10.4161/auto.6398.</ref>. This prevents cell functions and pathways from being damaged or interrupted by aggregates of proteins or non-functioning [[Organelles|organelles]], a key cause of disease. Diseases associated with abnormal autophagy include [[Parkinson's Disease|Parkinson's Disease]], osteoarthritis and cancer<ref>Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. The Journal of pathology. 2010;221(1):3-12. Available from: doi:10.1002/path.2697.</ref><ref>Levine, B. Cell biology: Autophagy and cancer. Nature. 2007;446:745-747. Available from: doi:10.1038/446745a.</ref>. Autophagy proceeds via a five-step mechanism that starts with the sequestration of cytosolic material by a double-membrane, known as a '[[Phagophore|phagophore]]'. Once the phagophore membrane ends fuse to form a vesicle, the substrate has been fully sequestered. Once sequestration is complete, the autophagosome fuses with a [[Lysosome|lysosome]] and up to 40 [[Hydrolytic enzymes|hydrolytic enzymes]] digest the autophagosome's cargo<ref>Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Tokyo 102-0075, Japan</ref>.  
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Autophagy is an essential cellular process, meaning 'self-eating', used by [[Cell|cells]] to degrade damaged and unnecessary cytosolic macromolecules and [[Organelles|organelles]], for example, [[Proteins|proteins]]<ref>Klionsky, DJ. Autophagy revisited: A conversation with Christian de Duve. Autophagy. 2008;4(6):740-3. Available from: DOI: 10.4161/auto.6398.</ref>. This prevents cell functions and pathways from being damaged, or interrupted, by protein aggregates or non-functioning [[Organelles|organelles]], a key cause of disease. It is also responsible for the removal of microbes, such as viruses and bacteria within the cell. Diseases associated with abnormal autophagy include [[Parkinson's Disease|Parkinson's Disease]], [[Ostearthritis|osteoarthritis]] and many forms of [[Cancer|cancers]] including associated bacterial cancers<ref>Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. The Journal of pathology. 2010;221(1):3-12. Available from: doi:10.1002/path.2697.</ref><ref>Levine, B. Cell biology: Autophagy and cancer. Nature. 2007;446:745-747. Available from: doi:10.1038/446745a.</ref>. Autophagy proceeds via a five-step mechanism that starts with the sequestration of cytosolic material by a double-membrane, known as a 'phagophore'. The phagophore membrane ends fuse, forming a specialised vesicle called an [[Autophagosome]]. Once sequestration is complete, the [[Autophagosome|autophagosome]] fuses with a [[Lysosome|lysosome]] and up to 40 [[Hydrolytic enzymes|hydrolytic enzymes]] digest the autophagosome's cargo<ref>Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Tokyo 102-0075, Japan</ref>.  
  
Autophagy helps the cell maintain a stable internal environment and prevents damage occurring to the cell/ tissues by removing harmful [[Molecules|molecules]] and preventing their accumulation<ref>Mizushima N. Autophagy: process and function. Genes &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp; Dev. 2007;21: 2861-2873. Available from: DOI:10.1101/gad.1599207.</ref>. It is extremely prominent in the case of starving cells where nutrients are required to perpetuate cell survival, or when the cell experiences other stresses such as hypoxia or drug treatment<ref>Yang Z J, Chee C E, Huang S, Sinicrope F A. The Role of Autophagy in Cancer: Therapeutic Implications. Molecular Cancer Therapeutics. 2011;10(9): 1533-1541. Available from: DOI: 10.1158/1535-7163.MCT-11-0047.</ref>.  
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Autophagy helps the cell maintain a stable internal environment, preventing damage to the cell and tissues by removing harmful [[Molecules|molecules]], stopping their accumulation<ref>Mizushima N. Autophagy: process and function. Genes and Dev. 2007;21: 2861-2873. Available from: DOI:10.1101/gad.1599207.</ref>. It is extremely prominent in the case of starving cells where nutrients are required to perpetuate cell survival, or when the cell experiences other stresses such as hypoxia or drug treatment<ref>Yang Z J, Chee C E, Huang S, Sinicrope F A. The Role of Autophagy in Cancer: Therapeutic Implications. Molecular Cancer Therapeutics. 2011;10(9): 1533-1541. Available from: DOI: 10.1158/1535-7163.MCT-11-0047.</ref>.  
  
One of the key products of autophagy, [[Amino acids|amino acids]], can be used for [[Anabolic processes|anabolic processes]] within the cell.  
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One of the key products of autophagy, [[Amino acids|amino acids]], can be used for anabolic processes. This is useful during starvation as autophagy is induced to provide the cell with needed nutrient supply<ref>Libin Shang, She Chen, Fenghe Du, Shen Li, Liping Zhao and Xiaodong Wanga. Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK.Proc Natl Acad Sci U S A. 2011 Mar 22; 108(12): 4788–4793.</ref>.  
  
Autophagy is controlled by mTOR (Mechanistic target of rapamycin), a kinase coded for by the MTOR gene. When mTOR is activated, autophagy is suppressed. mTOR can be suppressed by low amino acid concentrations, allowing autophagy to produce more amino acids.  
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Autophagy is controlled by mTOR (Mechanistic target of rapamycin), a [[Kinase|kinase]] coded for by the mTOR gene. When mTOR is active, autophagy is suppressed. However, mTOR can be suppressed by low amino acid concentrations, allowing autophagy to produce more amino acids.  
  
 
=== Types of autophagy  ===
 
=== Types of autophagy  ===
  
''Macroautophagy'' - widely considered to be the most used pathway of autophagy in the body. It deals with the recycling of dysfunctional organelles and proteins which may have been damaged or incorrectly folded during their synthesis. The process starts with a piece of cellular machinery termed the isolation membrane or “phagophore” which is a double membrane structure that elongates and encloses part of the cytoplasm as well as the target organelles or proteins. This structure is termed an “autophagosome”. The autophagosome then migrates to a lysosome to which it fuses with via the outer membrane. It is important to note the outer membrane stays intact thus keeping the contents and hydrolyses within the “autolysosome” for recycling<ref>Mizushima N, Komatsu M. Autophagy: Renovation of Cells and Tissues. Cell, 2011, Volume 147, Issue 4</ref>.  
+
''Macroautophagy'' - This is widely considered to be the most used pathway of autophagy in the body. It deals with the recycling of dysfunctional organelles and proteins which may have been damaged or incorrectly folded during their synthesis. The process starts with a piece of cellular machinery termed the isolation membrane or “phagophore”. This is a double membrane structure that elongates and encloses part of the cytoplasm, as well as the target organelles or proteins. The resulting specialised vesicle is termed an “autophagosome”. The autophagosome then migrates to a lysosome to which it fuses via the outer membrane. It is important to note the outer membrane stays intact thus keeping the contents and [[Hydrolases]] within the “autolysosome” for recycling<ref>Mizushima N, Komatsu M. Autophagy: Renovation of Cells and Tissues. Cell, 2011, Volume 147, Issue 4</ref><ref>Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. The Journal of Pathology. 2010; 221(1): 3-12. Available from: doi:  10.1002/path.2697</ref>.  
  
''Microautophagy'' - This differs from macroautophagy as it is only concerned with the degradation and recycling of cytoplasm. It also differs in its mechanism. No autophagosome is formed as the lysosome itself directly degrades the cytoplasm by inward invaginations in its membrane<ref>Li W, Li J, Bao J. Microautophagy: lesser-known self-eating. Cell and Molecular Life Science. 2012, Volume 69, 1125-1136.</ref>.
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==== Microautophagy ====
  
''Chaperone-mediated autophagy'' - only involves specific proteins within the cytoplasm. The target protein which is being degraded is recognised by a chaperone protein Hsc70 which binds to the target protein. This can then be recognised by specific receptors on the lysosomal membrane, unfolded and taken into the organelle for degradation<ref>Kaushik S, Cuervo AM. Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends in Cell Biology. 2012, Volume 22 Issue 8, 407-417</ref>.  
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This process differs from macroautophagy as it is only concerned with the degradation and recycling of cytoplasm in the cell. It also uses a different mechanism. No [[Autophagosome|autophagosome]] is formed as the [[Lysosome|lysosome]] itself directly degrades the cytoplasm by inward invaginations in its membrane<ref>Li W, Li J, Bao J. Microautophagy: lesser-known self-eating. Cell and Molecular Life Science. 2012, Volume 69, 1125-1136.</ref>.  
  
''Mitophagy'' - the selective degradation of mitochondria by autophagy. This is used by the cell in order to remove damaged mitochondria from the cell or as a mechanism to regulate the number of mitochondria present in the cell. This process is essential during some developmental processes, such as the maturation of reticulocytes since mature red blood cells do not contain any mitochondria; all the mitochondria present in the cell before differentiation must be removed<ref>Youle RJ, Narendra DP. Mechanisms of mitophagy. Nature Reviews Molecular Cell Biology. 2010; 12:9-14</ref>.<br>  
+
==== Chaperone-mediated autophagy ====
 +
Only involves specific proteins within the cytoplasm. The target protein which is being degraded is recognised by a chaperone protein Hsc70 which binds to the target protein. This can then be recognised by specific receptors on the lysosomal membrane, where it is unfolded and taken into the organelle for degradation<ref>Kaushik S, Cuervo AM. Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends in Cell Biology. 2012, Volume 22 Issue 8, 407-417</ref>.
 +
 
 +
==== Mitophagy ====
 +
The selective degradation of [[Mitochondria|mitochondria]] by autophagy. This is used by the cell to remove damaged mitochondria, or as a mechanism to regulate the number of mitochondria present in the cell. This process is essential during some developmental processes, such as the maturation of [[Reticulocyte|reticulocytes]], as [[Erythrocyte|mature red blood cells]] do not contain any mitochondria; all the mitochondria present in the cell before [[Differentiation|differentiation]] must be removed<ref>Youle RJ, Narendra DP. Mechanisms of mitophagy. Nature Reviews Molecular Cell Biology. 2010; 12:9-14</ref><ref>Deas E, Wood NW, Plun-Favreau H. Mitophagy and Parkinson’s disease: The PINK1-parkin link. Biochimica et Biophysica Acta. 2011; 1813(4): 623-633 Available from: doi:  10.1016/j.bbamcr.2010.08.007</ref>.
 +
 
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==== Xenophagy ====
 +
 
 +
Is the removal of intracellular pathogens from the cytosol or in pathogen-containing vacuoles. This process is essential to antibacterial and antiviral defences, as well as the immune response. Xenophagy has also been shown as a protective role of tumourigenesis. In a recent study in bacteria-associated cancer, of the gram-negative ''Helicobacter pylori''<ref>William Blahd, MD what Is H.pylori on December 06, 2016 [cited 19/11/18] Available from: https://www.webmd.com/digestive-disorders/h-pylori-helicobacter-pylori#2</ref>.
 +
 
 +
Autophagy has been a remarkable discovery. Knowing about the process of cell recycling has opened several possible therapeutic opportunities that will be a point of interest in research in the following years. Exploiting autophagy in humans can lead to delayed ageing and prevention of neurodegenerative and cancerous diseases. Further study will also educate us about how bacterial pathogens prevent autophagosomes from working effectively at the onset of a pathogenic invasion. This would lead to the understanding of countless bacterial diseases, and will hopefully provide an insight on how they can be cured. Therefore, the study on autophagic mechanisms needs to continue to have a better understanding of this remarkable process.
  
 
=== References  ===
 
=== References  ===
  
 
<references />
 
<references />

Latest revision as of 09:41, 10 December 2018

Autophagy is an essential cellular process, meaning 'self-eating', used by cells to degrade damaged and unnecessary cytosolic macromolecules and organelles, for example, proteins[1]. This prevents cell functions and pathways from being damaged, or interrupted, by protein aggregates or non-functioning organelles, a key cause of disease. It is also responsible for the removal of microbes, such as viruses and bacteria within the cell. Diseases associated with abnormal autophagy include Parkinson's Disease, osteoarthritis and many forms of cancers including associated bacterial cancers[2][3]. Autophagy proceeds via a five-step mechanism that starts with the sequestration of cytosolic material by a double-membrane, known as a 'phagophore'. The phagophore membrane ends fuse, forming a specialised vesicle called an Autophagosome. Once sequestration is complete, the autophagosome fuses with a lysosome and up to 40 hydrolytic enzymes digest the autophagosome's cargo[4].

Autophagy helps the cell maintain a stable internal environment, preventing damage to the cell and tissues by removing harmful molecules, stopping their accumulation[5]. It is extremely prominent in the case of starving cells where nutrients are required to perpetuate cell survival, or when the cell experiences other stresses such as hypoxia or drug treatment[6].

One of the key products of autophagy, amino acids, can be used for anabolic processes. This is useful during starvation as autophagy is induced to provide the cell with needed nutrient supply[7].

Autophagy is controlled by mTOR (Mechanistic target of rapamycin), a kinase coded for by the mTOR gene. When mTOR is active, autophagy is suppressed. However, mTOR can be suppressed by low amino acid concentrations, allowing autophagy to produce more amino acids.

Contents

Types of autophagy

Macroautophagy - This is widely considered to be the most used pathway of autophagy in the body. It deals with the recycling of dysfunctional organelles and proteins which may have been damaged or incorrectly folded during their synthesis. The process starts with a piece of cellular machinery termed the isolation membrane or “phagophore”. This is a double membrane structure that elongates and encloses part of the cytoplasm, as well as the target organelles or proteins. The resulting specialised vesicle is termed an “autophagosome”. The autophagosome then migrates to a lysosome to which it fuses via the outer membrane. It is important to note the outer membrane stays intact thus keeping the contents and Hydrolases within the “autolysosome” for recycling[8][9].

Microautophagy

This process differs from macroautophagy as it is only concerned with the degradation and recycling of cytoplasm in the cell. It also uses a different mechanism. No autophagosome is formed as the lysosome itself directly degrades the cytoplasm by inward invaginations in its membrane[10].

Chaperone-mediated autophagy

Only involves specific proteins within the cytoplasm. The target protein which is being degraded is recognised by a chaperone protein Hsc70 which binds to the target protein. This can then be recognised by specific receptors on the lysosomal membrane, where it is unfolded and taken into the organelle for degradation[11].

Mitophagy

The selective degradation of mitochondria by autophagy. This is used by the cell to remove damaged mitochondria, or as a mechanism to regulate the number of mitochondria present in the cell. This process is essential during some developmental processes, such as the maturation of reticulocytes, as mature red blood cells do not contain any mitochondria; all the mitochondria present in the cell before differentiation must be removed[12][13].

Xenophagy

Is the removal of intracellular pathogens from the cytosol or in pathogen-containing vacuoles. This process is essential to antibacterial and antiviral defences, as well as the immune response. Xenophagy has also been shown as a protective role of tumourigenesis. In a recent study in bacteria-associated cancer, of the gram-negative Helicobacter pylori[14].

Autophagy has been a remarkable discovery. Knowing about the process of cell recycling has opened several possible therapeutic opportunities that will be a point of interest in research in the following years. Exploiting autophagy in humans can lead to delayed ageing and prevention of neurodegenerative and cancerous diseases. Further study will also educate us about how bacterial pathogens prevent autophagosomes from working effectively at the onset of a pathogenic invasion. This would lead to the understanding of countless bacterial diseases, and will hopefully provide an insight on how they can be cured. Therefore, the study on autophagic mechanisms needs to continue to have a better understanding of this remarkable process.

References

  1. Klionsky, DJ. Autophagy revisited: A conversation with Christian de Duve. Autophagy. 2008;4(6):740-3. Available from: DOI: 10.4161/auto.6398.
  2. Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. The Journal of pathology. 2010;221(1):3-12. Available from: doi:10.1002/path.2697.
  3. Levine, B. Cell biology: Autophagy and cancer. Nature. 2007;446:745-747. Available from: doi:10.1038/446745a.
  4. Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Tokyo 102-0075, Japan
  5. Mizushima N. Autophagy: process and function. Genes and Dev. 2007;21: 2861-2873. Available from: DOI:10.1101/gad.1599207.
  6. Yang Z J, Chee C E, Huang S, Sinicrope F A. The Role of Autophagy in Cancer: Therapeutic Implications. Molecular Cancer Therapeutics. 2011;10(9): 1533-1541. Available from: DOI: 10.1158/1535-7163.MCT-11-0047.
  7. Libin Shang, She Chen, Fenghe Du, Shen Li, Liping Zhao and Xiaodong Wanga. Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK.Proc Natl Acad Sci U S A. 2011 Mar 22; 108(12): 4788–4793.
  8. Mizushima N, Komatsu M. Autophagy: Renovation of Cells and Tissues. Cell, 2011, Volume 147, Issue 4
  9. Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. The Journal of Pathology. 2010; 221(1): 3-12. Available from: doi: 10.1002/path.2697
  10. Li W, Li J, Bao J. Microautophagy: lesser-known self-eating. Cell and Molecular Life Science. 2012, Volume 69, 1125-1136.
  11. Kaushik S, Cuervo AM. Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends in Cell Biology. 2012, Volume 22 Issue 8, 407-417
  12. Youle RJ, Narendra DP. Mechanisms of mitophagy. Nature Reviews Molecular Cell Biology. 2010; 12:9-14
  13. Deas E, Wood NW, Plun-Favreau H. Mitophagy and Parkinson’s disease: The PINK1-parkin link. Biochimica et Biophysica Acta. 2011; 1813(4): 623-633 Available from: doi: 10.1016/j.bbamcr.2010.08.007
  14. William Blahd, MD what Is H.pylori on December 06, 2016 [cited 19/11/18] Available from: https://www.webmd.com/digestive-disorders/h-pylori-helicobacter-pylori#2
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