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Mol Biol Cell. 2017 Mar 1;28(5):600-612. doi: 10.1091/mbc.E16-07-0545. Epub 2017 Jan 5.

Rapid degradation of mutant SLC25A46 by the ubiquitin-proteasome system results in MFN1/2-mediated hyperfusion of mitochondria.

Author information

1
Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095.
2
Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095.
3
Department of Neurology, University of California, Los Angeles, Los Angeles, CA 90095.
4
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
5
Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095.
6
Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095 koehler@chem.ucla.edu.
7
Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095.

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.

PMID:
28057766
PMCID:
PMC5328619
DOI:
10.1091/mbc.E16-07-0545
[Indexed for MEDLINE]
Free PMC Article

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