Pink/Parkin Mediated Mitophagy

Stable Identifier
R-HSA-5205685
Type
Pathway
Species
Homo sapiens
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This is the process of selective removal of damaged mitochondria by autophagosomes and subsequent catabolism by lysosomes. In healthy mitochondria, PINK1 is imported to the inner mitochondrial membrane, presumably through the TOM/TIM complex. The TIM complex associated protease, mitochondrial MPP, cleaves PINK1 mitochondrial targeting sequence (MTS). PINK1 may be cleaved by the inner membrane presenilin associated rhomboid like protease (PARL) and ultimately proteolytically degraded. Loss of membrane potential in damaged mitochondria prevents the import of the PTEN induced putative kinase 1 (PINK1) which accumulates in the defective mitochondria triggering the recruitment of the E3 ubiquitin protein ligase (Parkin). Once on the mitochondria, Parkin promotes the ubiquitination of mitochondrial substrates embedded in the OMM such as the mitofusin Mitochondrial Assembly Regulatory Factor (MARF), mitofusin 1 and 2 (Mfn1, 2) and the Voltage Dependent Anion Channel 1 (VDAC1). After the ubiquitination events, p62 is recruited to mitochondria, binding the Parkin ubiquitinated substrates, linking the ubiquitinated substrates to the Microtubule associated protein Autophagy marker Light Chain 3 (LC3). Targeting the entire mitochondria for autophagic degradation. The recruitment of LC3 complexes with the autophagosome membrane and the AuTophaGy proteins 5 12 (Atg5 Atg12) complex. The mitochondria is engulfed after the isolation membrane grows to a sufficient size to engulf the mitochondria. Once autophagic vesicle formation is complete, vesicle fusion with lysosomes occurs to form autophagolysosomes in which the lysosomal hydrolases (cathepsins and lipases) degrade the intra autophagosomal content. Cathepsin also degrades LC3 on the intra autophagosomal surface of the autophagic vesicle.

Literature References
PubMed ID Title Journal Year
21179058 Mechanisms of mitophagy

Youle, RJ, Narendra, DP

Nat. Rev. Mol. Cell Biol. 2011
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Orthologous Events
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