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Chen, Y and Dorn, GW 2nd (2013) PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science 340:471-5

Senescent and damaged mitochondria undergo selective mitophagic elimination through mechanisms requiring two Parkinson's disease factors, the mitochondrial kinase PINK1 (PTEN-induced putative kinase protein 1; PTEN is phosphatase and tensin homolog) and the cytosolic ubiquitin ligase Parkin. The nature of the PINK-Parkin interaction and the identity of key factors directing Parkin to damaged mitochondria are unknown. We show that the mitochondrial outer membrane guanosine triphosphatase mitofusin (Mfn) 2 mediates Parkin recruitment to damaged mitochondria. Parkin bound to Mfn2 in a PINK1-dependent manner; PINK1 phosphorylated Mfn2 and promoted its Parkin-mediated ubiqitination. Ablation of Mfn2 in mouse cardiac myocytes prevented depolarization-induced translocation of Parkin to the mitochondria and suppressed mitophagy. Accumulation of morphologically and functionally abnormal mitochondria induced respiratory dysfunction in Mfn2-deficient mouse embryonic fibroblasts and cardiomyocytes and in Parkin-deficient Drosophila heart tubes, causing dilated cardiomyopathy. Thus, Mfn2 functions as a mitochondrial receptor for Parkin and is required for quality control of cardiac mitochondria.

PubMed PMC3774525 Online version:10.1126/science.1231031

Amino Acid Sequence; Animals; Autophagy; Cardiomyopathies/enzymology; Drosophila melanogaster; Fibroblasts/ultrastructure; GTP Phosphohydrolases/genetics; GTP Phosphohydrolases/metabolism; HEK293 Cells; Humans; Mice; Mice, Mutant Strains; Mitochondria/enzymology; Mitochondria, Heart/enzymology; Molecular Sequence Data; Myocytes, Cardiac/enzymology; Myocytes, Cardiac/ultrastructure; Phosphorylation; Protein Kinases/metabolism; Ubiquitin-Protein Ligases/metabolism; Ubiquitination