PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria
- PMID: 23620051
- PMCID: PMC3774525
- DOI: 10.1126/science.1231031
PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria
Abstract
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.
Figures
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Comment in
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Mitophagy: mitofusin recruits a mitochondrial killer.Curr Biol. 2013 Jul 8;23(13):R570-2. doi: 10.1016/j.cub.2013.05.032. Curr Biol. 2013. PMID: 23845246
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