title: Rapid degradation of mutant SLC25A46 by the ubiquitin-proteasome system results in MFN1/2-mediated hyperfusion of mitochondria.
abstract: SCL25A46 is a mitochondrial carrier protein that surprisingly localizes to the outer membrane and is distantly related to Ugo1. Here we show that a subset of SLC25A46 interacts with mitochondrial dynamics components and the MICOS complex. Decreased expression of SLC25A46 results in increased stability and oligomerization of MFN1 and MFN2 on mitochondria, promoting mitochondrial hyperfusion. A mutation at L341P causes rapid degradation of SLC25A46, which manifests as a rare disease, pontocerebellar hypoplasia. The E3 ubiquitin ligases MULAN and MARCH5 coordinate ubiquitylation of SLC25A46 L341P, leading to degradation by organized activities of P97 and the proteasome. Whereas outer mitochondrial membrane-associated degradation is typically associated with apoptosis or a specialized type of autophagy termed mitophagy, SLC25A46 degradation operates independently 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 independently of mitophagy and apoptosis, providing a framework for mechanistic studies in the proteolysis of outer membrane proteins.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: Janos
authors.initials: J
authors.lastname: Steffen
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: Ajay A
authors.initials: AA
authors.lastname: Vashisht
authors.affiliation: Department of Neurology, University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: Jijun
authors.initials: J
authors.lastname: Wan
authors.affiliation: Department of Neurology, University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: Joanna C
authors.initials: JC
authors.lastname: Jen
authors.affiliation: Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Claypool
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095.|Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: James A
authors.initials: JA
authors.lastname: Wohlschlegel
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095 koehler@chem.ucla.edu.|Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095.|Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: Carla M
authors.initials: CM
authors.lastname: Koehler
mesh_terms: D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000502:physiology; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D028061:Phosphate Transport Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D028061:Phosphate Transport Proteins; C584459:SLC25A46 protein, human; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; C470017:Mfn1 protein, human