A novel mitochondrial ubiquitin ligase involved in the regulation of mitochondrial fusion

Abstract

Mitochondrial protein quality control is one of the mechanisms that protect mitochondrial integrity. Recognition of terminally misfolded proteins is achieved through outer mitochondrial membrane‐associated degradation (OMMAD). Misfolded proteins are ubiquitinated, retrotranslocated by the AAA‐ATPase p97 and then degraded by the proteasome. OMMAD ubiquitin ligases such as MARCH5, Parkin and IBRDC2 are key proteins in the control of mitochondrial fission, mitophagy and apoptosis, respectively. We describe an ubiquitin‐ligase (RTM9) which is localized on the outer mitochondrial membrane. RTM9 consists of transmembrane domains and a RING finger domain, exposed to the cytosol. In an ubiquitination assay RTM9 shows E3 ubiquitin ligase activity. RTM9 is a novel regulator of mitochondrial fusion: while expression of wildtype RTM9 had no effect on mitochondrial morphology, expression of RTM9RING‐ resulted in the fragmentation of the mitochondrial network. In addition, RTM9 interacts with both mitofusins, Mfn1 and Mfn2, suggesting a role for RTM9 in the regulation of mitochondrial fusion.Taken together, RTM9 is a novel mitochondrial ubiquitin ligase involved in the regulation of mitochondrial fusion potentially playing a critical role during mitochondrial quality control.