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Pink/Parkin Mediated Mitophagy

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.

from REACTOME source record: R-HSA-5205685
Type: pathway
Taxonomic scope
:
organism-specific biosystem
Organism
:
Homo sapiens
BSID:
1309219

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