PINK1- Phosphorylated Mitofusin 2 is a Parkin Receptor for Culling Damaged Mitochondria

By Yun Chen, Gerald W. Dorn II. Science, 2013

1,258 citations recorded by the source corpus.

Where Parkin Parks Damaged mitochondria are removed from cells in a process known as mitophagy. Failure of this quality-control mechanism contributes to Parkinson's disease. When damaged mitochondria lose membrane depolarization, the protein kinase, PINK1, accumulates on the mitochondrial surface, recruits Parkin, and promotes mitophagy. Chen and Dorn (p. 471) describe another component of this process, mitofusin 2, which appears to function as the receptor for Parkin on the surface of damaged mitochondria. The Parkinson’s disease factors PINK1 and Parkin interact with mitofusin 2 on damaged mitochondria. 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.

Subfields: Cellular and Molecular Neuroscience, Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/ffa518779b9ac15bc2a6d45a16f8b08c7b012fcc

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Citations in the corpus

The Roles of PINK1, Parkin and Mitochondrial Fidelity in Parkinson's Disease (2015, background): “Mitofusin2 (Mfn2), a protein involved in OMM fusion, was identified to be phosphorylated at Thr111 and Ser442 by PINK1 to induce Mfn2 binding to Parkin and initiate Mfn2 ubiquitination and degradation (Chen and Dorn, 2013).”
Deciphering the Molecular Signals of PINK1/Parkin Mitophagy. (2016, background): “The mitochondrial fusion mediator Mfn2 has also been reported to function as a receptor for Parkin in cardiac cells [76].”
Hallmarks of Cellular Senescence. (2018, positive): “deficiency in Mfn2 causes mitochondrial dysfunction in mouse embryonic fibroblasts and cardiomyocytes [147].”
Autophagy and Mitophagy in Cardiovascular Disease. (2017, background): “The deletion of park (the fly ortholog of PARK2) in Drosophila melanogaster also caused dilated cardiomyopathy that could be rescued by park re-expression in cardiomyocytes.(21,22) Conversely, and at odds with the observation that the cardiomyocyte-specific deletion of Park2 at birth provokes perina”