Abstract
Mutations in mitofusin 2 (MFN2) that are associated with the pathology of the debilitating neuropathy Charcot-Marie-Tooth type 2A (CMT2A) are known to alter mitochondrial morphology. One such abundant MFN2 mutation, R364W, results in the generation of elongated, interconnected mitochondria. However, the mechanism leading to this mitochondrial aberration remains poorly understood. Here, we show that mitochondrial hyperfusion in the presence of R364W-MFN2 is due to increased degradation of DRP1 (also known as DNM1L). The E3 ubiquitin ligase MITOL (also known as MARCHF5) is known to ubiquitylate both MFN2 and DRP1. Interaction with and subsequent ubiquitylation by MITOL is stronger in the presence of wild-type MFN2 than with R364W-MFN2. This differential interaction of MITOL with MFN2 in the presence of R364W-MFN2 renders the ligase more available for DRP1 ubiquitylation. Multi-monoubiquitylation and proteasomal degradation of DRP1 in R364W-MFN2 cells in the presence of MITOL eventually leads to mitochondrial hyperfusion. Here, we provide a mechanistic insight into mitochondrial hyperfusion, while also reporting that MFN2 can indirectly modulate DRP1 - an effect not shown previously. This article has an associated First Person interview with the first author of the paper.