Indexed on: 07 Jan '17Published on: 07 Jan '17Published in: Molecular biology of the cell
SCL25A46 is a member of the mitochondrial carrier protein that surprisingly localizes to the outer membrane and is distantly related to Ugo1. Here we show that a subset of SLC25A46 interacted with mitochondrial dynamics components and the MICOS complex. Decreased expression of SLC25A46 resulted in increased stability and oligomerization of MFN1 and MFN2 on mitochondria, promoting mitochondrial hyperfusion. A mutation at L341P caused rapid degradation of SLC25A46 that manifested as a rare disease, pontocerebellar hypoplasia. The E3 ubiquitin ligases MULAN and MARCH5 coordinated ubiquitylation of SLC25A46 L341P, leading to degradation by organized activities of P97 and the proteasome. Whereas outer mitochondrial membrane-associated degradation (OMMAD) is typically associated with apoptosis or a specialized type of autophagy, termed mitophagy, SLC25A46 degradation operated independent of activation of outer membrane stress pathways. Thus, SLC25A46 is a new component in mitochondrial dynamics that serves as a regulator for MFN1/2 oligomerization. Moreover, SLC25A46 is selectively degraded from the outer membrane, independent of mitophagy and apoptosis, providing a framework for mechanistic studies in the proteolysis of outer membrane proteins.