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

TLDR

Mitophagic elimination of senescent or damaged mitochondria depends on the kinase PINK1 and the ubiquitin ligase Parkin, yet the specific interaction between them and the factors that recruit Parkin remain unclear. We demonstrate that PINK1‑phosphorylated mitofusin‑2 acts as a Parkin receptor, recruiting Parkin to damaged mitochondria and enabling mitophagy; loss of Mfn2 impairs Parkin recruitment, blocks mitophagy, and causes mitochondrial dysfunction and dilated cardiomyopathy.

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.