Mitophagy (Homo sapiens)

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51, 2, 634441, 2, 622cytosolmitochondrial inner membranephagocytic vesiclemitochondrial outer membraneSQSTM1 K48polyUb-VDAC1MAP1LC3B K48polyUb-MFN2 K48polyUb-MFN1 ATG12 MAP1LC3B ATG5 TOMM7 K48polyUb-VDAC1 MFN2VDAC1K48polyUb-MFN1 PINK1 MAP1LC3B K48polyUb-VDAC1 TOMM5 K48polyUb-MTERFD1 ATG5:ATG12K48polyUB MitophagySubstrates:SQSTM1TOMM6 K48polyUb-MFN1PINK1PARK2:PINK1K48polyUb-MFN2 ATG12 MTERFD1K48polyUb-MTERFD1 SQSTM1MFN1ATG5 SQSTM1 K48polyUb-MFN1 TOMM40 PINK1K48polyUb-MTERFD1TOMM40 ComplexMAP1LC3A SQSTM1 ATG5:ATG12:LC3:K48polyUB Mitophagy Substrates:SQSTM1LC3TOMM70A PARK2TOMM22 K48polyUb-VDAC1 TOMM20 K48polyUb-MTERFD1 LC3:K48polyUBMitophagySubstrates:SQSTM1PINK1(111-581)PINK1MAP1LC3A MAP1LC3A PARK2 K48polyUb-MFN2K48polyUb-MFN2


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

 

Bibliography

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  1. Youle RJ, Narendra DP.; ''Mechanisms of mitophagy.''; PubMed Europe PMC Scholia
  2. 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
  3. Tanida I.; ''Autophagosome formation and molecular mechanism of autophagy.''; PubMed Europe PMC Scholia
  4. Narendra DP, Youle RJ.; ''Targeting mitochondrial dysfunction: role for PINK1 and Parkin in mitochondrial quality control.''; PubMed Europe PMC Scholia
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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

History

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CompareRevisionActionTimeUserComment
115006view16:54, 25 January 2021ReactomeTeamReactome version 75
113450view11:52, 2 November 2020ReactomeTeamReactome version 74
112650view16:03, 9 October 2020ReactomeTeamReactome version 73
101565view11:43, 1 November 2018ReactomeTeamreactome version 66
101101view21:26, 31 October 2018ReactomeTeamreactome version 65
100630view20:01, 31 October 2018ReactomeTeamreactome version 64
100180view16:45, 31 October 2018ReactomeTeamreactome version 63
99730view15:12, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99301view12:46, 31 October 2018ReactomeTeamreactome version 62
93834view13:39, 16 August 2017ReactomeTeamreactome version 61
93388view11:22, 9 August 2017ReactomeTeamreactome version 61
87965view13:14, 25 July 2016RyanmillerOntology Term : 'regulatory pathway' added !
86474view09:19, 11 July 2016ReactomeTeamreactome version 56
83439view12:25, 18 November 2015ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ATG12 ProteinO94817 (Uniprot-TrEMBL)
ATG5 ProteinQ9H1Y0 (Uniprot-TrEMBL)
ATG5:ATG12:LC3:K48polyUB Mitophagy Substrates:SQSTM1ComplexR-HSA-5205648 (Reactome)
ATG5:ATG12ComplexR-HSA-5205638 (Reactome)
K48polyUB Mitophagy Substrates:SQSTM1ComplexR-HSA-5205659 (Reactome)
K48polyUb-MFN1 ProteinQ8IWA4 (Uniprot-TrEMBL)
K48polyUb-MFN1ProteinQ8IWA4 (Uniprot-TrEMBL)
K48polyUb-MFN2 ProteinO95140 (Uniprot-TrEMBL)
K48polyUb-MFN2ProteinO95140 (Uniprot-TrEMBL)
K48polyUb-MTERFD1 ProteinQ96E29 (Uniprot-TrEMBL)
K48polyUb-MTERFD1ProteinQ96E29 (Uniprot-TrEMBL)
K48polyUb-VDAC1 ProteinP21796 (Uniprot-TrEMBL)
K48polyUb-VDAC1ProteinP21796 (Uniprot-TrEMBL)
LC3:K48polyUB

Mitophagy

Substrates:SQSTM1		ComplexR-HSA-5205670 (Reactome)
LC3ComplexR-HSA-5205658 (Reactome)
MAP1LC3A ProteinQ9H492 (Uniprot-TrEMBL)
MAP1LC3B ProteinQ9GZQ8 (Uniprot-TrEMBL)
MFN1ProteinQ8IWA4 (Uniprot-TrEMBL)
MFN2ProteinO95140 (Uniprot-TrEMBL)
MTERFD1ProteinQ96E29 (Uniprot-TrEMBL)
PARK2 ProteinO60260 (Uniprot-TrEMBL)
PARK2:PINK1ComplexR-HSA-5205683 (Reactome)
PARK2ProteinO60260 (Uniprot-TrEMBL)
PINK1 ProteinQ9BXM7 (Uniprot-TrEMBL)
PINK1(111-581)ProteinQ9BXM7 (Uniprot-TrEMBL)
PINK1ProteinQ9BXM7 (Uniprot-TrEMBL)
SQSTM1 ProteinQ13501 (Uniprot-TrEMBL)
SQSTM1ProteinQ13501 (Uniprot-TrEMBL)
TOMM20 ProteinQ15388 (Uniprot-TrEMBL)
TOMM22 ProteinQ9NS69 (Uniprot-TrEMBL)
TOMM40 ComplexComplexR-HSA-1252240 (Reactome)
TOMM40 ProteinO96008 (Uniprot-TrEMBL)
TOMM5 ProteinQ8N4H5 (Uniprot-TrEMBL)
TOMM6 ProteinQ96B49 (Uniprot-TrEMBL)
TOMM7 ProteinQ9P0U1 (Uniprot-TrEMBL)
TOMM70A ProteinO94826 (Uniprot-TrEMBL)
VDAC1ProteinP21796 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ATG5:ATG12:LC3:K48polyUB Mitophagy Substrates:SQSTM1ArrowR-HSA-5205663 (Reactome)
ATG5:ATG12R-HSA-5205663 (Reactome)
K48polyUB Mitophagy Substrates:SQSTM1ArrowR-HSA-5205673 (Reactome)
K48polyUB Mitophagy Substrates:SQSTM1R-HSA-5205649 (Reactome)
K48polyUb-MFN1ArrowR-HSA-5205682 (Reactome)
K48polyUb-MFN1R-HSA-5205673 (Reactome)
K48polyUb-MFN2ArrowR-HSA-5205682 (Reactome)
K48polyUb-MFN2R-HSA-5205673 (Reactome)
K48polyUb-MTERFD1ArrowR-HSA-5205682 (Reactome)
K48polyUb-MTERFD1R-HSA-5205673 (Reactome)
K48polyUb-VDAC1ArrowR-HSA-5205682 (Reactome)
K48polyUb-VDAC1R-HSA-5205673 (Reactome)
LC3:K48polyUB

Mitophagy

Substrates:SQSTM1		ArrowR-HSA-5205649 (Reactome)
LC3:K48polyUB

Mitophagy

Substrates:SQSTM1		R-HSA-5205663 (Reactome)
LC3R-HSA-5205649 (Reactome)
MFN1R-HSA-5205682 (Reactome)
MFN2R-HSA-5205682 (Reactome)
MTERFD1R-HSA-5205682 (Reactome)
PARK2:PINK1ArrowR-HSA-5205652 (Reactome)
PARK2:PINK1mim-catalysisR-HSA-5205682 (Reactome)
PARK2R-HSA-5205652 (Reactome)
PINK1(111-581)ArrowR-HSA-5205681 (Reactome)
PINK1ArrowR-HSA-5205661 (Reactome)
PINK1ArrowR-HSA-5205672 (Reactome)
PINK1R-HSA-5205652 (Reactome)
PINK1R-HSA-5205661 (Reactome)
PINK1R-HSA-5205672 (Reactome)
PINK1R-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.
SQSTM1R-HSA-5205673 (Reactome)
TOMM40 Complexmim-catalysisR-HSA-5205661 (Reactome)
VDAC1R-HSA-5205682 (Reactome)
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