Mitophagy (Homo sapiens)
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Description
Mitophagy is a specific form of autophagy where mitochondria are specifically targeted for degradation by autophagolysosomes.. In mammals there are a number of known mechanisms of mitophagy. One insures maternal inheritance of mitochondrial DNA through the elimination of sperm derived mitochondria. A second is elimination of functional mitochondria during erythrocyte maturation and eye lens maturation. It is established that the outer mitochondrial membrane receptor Nix (or Bnip3l) and autophagosome associated protein LC3 are important for mitochondrial degradation in erythrocytes. A third mechanism is driven by the Pink1 and Parkin proteins. Parkin is recruited to the mitochondria when the mitochondrial membrane potential is reduced due to uncoupling, thereby initiating mitophagy.
View original pathway at:Reactome.
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Ontology Terms
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- Youle RJ, Narendra DP.; ''Mechanisms of mitophagy.''; PubMed Europe PMC Scholia
- Sun F, Kanthasamy A, Anantharam V, Kanthasamy AG.; ''Mitochondrial accumulation of polyubiquitinated proteins and differential regulation of apoptosis by polyubiquitination sites Lys-48 and -63.''; PubMed Europe PMC Scholia
- Tanida I.; ''Autophagosome formation and molecular mechanism of autophagy.''; PubMed Europe PMC Scholia
- Narendra DP, Youle RJ.; ''Targeting mitochondrial dysfunction: role for PINK1 and Parkin in mitochondrial quality control.''; PubMed Europe PMC Scholia
- Chen G, Han Z, Feng D, Chen Y, Chen L, Wu H, Huang L, Zhou C, Cai X, Fu C, Duan L, Wang X, Liu L, Liu X, Shen Y, Zhu Y, Chen Q.; ''A regulatory signaling loop comprising the PGAM5 phosphatase and CK2 controls receptor-mediated mitophagy.''; PubMed Europe PMC Scholia
- Wu W, Tian W, Hu Z, Chen G, Huang L, Li W, Zhang X, Xue P, Zhou C, Liu L, Zhu Y, Zhang X, Li L, Zhang L, Sui S, Zhao B, Feng D.; ''ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy.''; PubMed Europe PMC Scholia
- Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, Cookson MR, Youle RJ.; ''PINK1 is selectively stabilized on impaired mitochondria to activate Parkin.''; PubMed Europe PMC Scholia
- Jin SM, Lazarou M, Wang C, Kane LA, Narendra DP, Youle RJ.; ''Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL.''; PubMed Europe PMC Scholia
- Liu L, Feng D, Chen G, Chen M, Zheng Q, Song P, Ma Q, Zhu C, Wang R, Qi W, Huang L, Xue P, Li B, Wang X, Jin H, Wang J, Yang F, Liu P, Zhu Y, Sui S, Chen Q.; ''Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells.''; PubMed Europe PMC Scholia
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External references
DataNodes
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Annotated Interactions
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| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| ATG5:ATG12:LC3:K48polyUB Mitophagy Substrates:SQSTM1 | Arrow | R-HSA-5205663 (Reactome)  | ||
| ATG5:ATG12 | R-HSA-5205663 (Reactome) | |||
| K48polyUB Mitophagy Substrates:SQSTM1 | Arrow | R-HSA-5205673 (Reactome) | ||
| K48polyUB Mitophagy Substrates:SQSTM1 | R-HSA-5205649 (Reactome) | |||
| K48polyUb-MFN1 | Arrow | R-HSA-5205682 (Reactome) | ||
| K48polyUb-MFN1 | R-HSA-5205673 (Reactome) | |||
| K48polyUb-MFN2 | Arrow | R-HSA-5205682 (Reactome) | ||
| K48polyUb-MFN2 | R-HSA-5205673 (Reactome) | |||
| K48polyUb-MTERFD1 | Arrow | R-HSA-5205682 (Reactome) | ||
| K48polyUb-MTERFD1 | R-HSA-5205673 (Reactome) | |||
| K48polyUb-VDAC1 | Arrow | R-HSA-5205682 (Reactome) | ||
| K48polyUb-VDAC1 | R-HSA-5205673 (Reactome) | |||
| LC3:K48polyUB
Mitophagy Substrates:SQSTM1 | Arrow | R-HSA-5205649 (Reactome) | ||
| LC3:K48polyUB
Mitophagy Substrates:SQSTM1 | R-HSA-5205663 (Reactome) | |||
| LC3 | R-HSA-5205649 (Reactome) | |||
| MFN1 | R-HSA-5205682 (Reactome) | |||
| MFN2 | R-HSA-5205682 (Reactome) | |||
| MTERFD1 | R-HSA-5205682 (Reactome) | |||
| PARK2:PINK1 | Arrow | R-HSA-5205652 (Reactome) | ||
| PARK2:PINK1 | mim-catalysis | R-HSA-5205682 (Reactome) | ||
| PARK2 | R-HSA-5205652 (Reactome) | |||
| PINK1(111-581) | Arrow | R-HSA-5205681 (Reactome) | ||
| PINK1 | Arrow | R-HSA-5205661 (Reactome) | ||
| PINK1 | Arrow | R-HSA-5205672 (Reactome) | ||
| PINK1 | R-HSA-5205652 (Reactome) | |||
| PINK1 | R-HSA-5205661 (Reactome) | |||
| PINK1 | R-HSA-5205672 (Reactome) | |||
| PINK1 | R-HSA-5205681 (Reactome) | |||
| R-HSA-5205649 (Reactome) | p62 links to the microtubule-associated protein Autophagy marker Light Chain 3 (LC3). This begins the recruitment of the autophagy machinery to the damaged mitochondria, targeting it for autophagic degradation. | |||
| R-HSA-5205652 (Reactome) | Parkin promotes the ubiquitination of outer mitochondrial membrane emedded proteins including the mitofusin mitochondrial assembly regulatory factor (MARF), mitofusin 1, mitofusin 2 and voltage dependent anion selective channel protein 1 (vDAC1). | |||
| R-HSA-5205661 (Reactome) | PINK1 is constitutively synthesized and imported into all mitochondria. In healthy mitochondria PINK1 is cleaved by voltage-sensitive proteolysis. | |||
| R-HSA-5205663 (Reactome) | The mitochondria are engulfed after elongation of the isolation membrane. Once the autophagosome is formed, its outer membrane fuses with lysosomes to form the autolysosome. The lysosomal hydrolases (cathepsins and lipases) ultimately degrade the damaged mitochondria and its associated proteins. | |||
| R-HSA-5205672 (Reactome) | On damaged mitochondria that have lost their membrane potential, however, PINK1 cleavage is inhibited, leading to high PINK1 protein accumulation on the inner leaf of the OMM of dysfunctional mitochondria. Full-length mitochondrial PINK1 is the active form in the PINK1/Parkin pathway. | |||
| R-HSA-5205673 (Reactome) | After the ubiquitination events, p62 is recruited to mitochondria, binding the Parkin-ubiquitinated substrates | |||
| R-HSA-5205681 (Reactome) | Full-length PINK1 (63 kDa), which is in the inner mitochondrial space, is proteolytically cleaved into an 52-kDa cytosolic fragment (111 - 581) that is released back into the cytoplasm by an unknown mechanism and degraded by the proteasome. cleavage of PINK1 into an unstable cytosolic form maintains low levels of PINK1 on healthy mitochondria in order to suppress the PINK1/Parkin pathway in the absence of mitochondrial damage. At present, not all of the proteases mediating the cleavage of PINK1 in mammalian cells have been identified. | |||
| R-HSA-5205682 (Reactome) | Parkin promotes the ubiquitination of the mitofusin mitochondrial assembly regulatory factor (MARF), mitofusin 1, mitofusin 2 and voltage-dependent anion-selective channel protein 1 (vDAC1), all of which are embedded in the OMM. | |||
| SQSTM1 | R-HSA-5205673 (Reactome) | |||
| TOMM40 Complex | mim-catalysis | R-HSA-5205661 (Reactome) | ||
| VDAC1 | R-HSA-5205682 (Reactome) |
