Inhibition of Proteasome Rescues a Pathogenic Variant of Respiratory Chain Assembly Factor COA7

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2019 Mar 20

PMID 30885959

Citations 34

Authors

Karthik Mohanraj

Michal Wasilewski

Cristiane Beninca

Dominik Cysewski

Jaroslaw Poznanski

Paulina Sakowska

Zaneta Bugajska

Markus Deckers

Sven Dennerlein

Erika Fernandez-Vizarra

Peter Rehling

Michal Dadlez

Massimo Zeviani

Agnieszka Chacinska

Affiliations

Soon will be listed here.

Abstract

Nuclear and mitochondrial genome mutations lead to various mitochondrial diseases, many of which affect the mitochondrial respiratory chain. The proteome of the intermembrane space (IMS) of mitochondria consists of several important assembly factors that participate in the biogenesis of mitochondrial respiratory chain complexes. The present study comprehensively analyzed a recently identified IMS protein cytochrome oxidase assembly factor 7 (COA7), or RESpiratory chain Assembly 1 (RESA1) factor that is associated with a rare form of mitochondrial leukoencephalopathy and complex IV deficiency. We found that COA7 requires the mitochondrial IMS import and assembly (MIA) pathway for efficient accumulation in the IMS We also found that pathogenic mutant versions of COA7 are imported slower than the wild-type protein, and mislocalized proteins are degraded in the cytosol by the proteasome. Interestingly, proteasome inhibition rescued both the mitochondrial localization of COA7 and complex IV activity in patient-derived fibroblasts. We propose proteasome inhibition as a novel therapeutic approach for a broad range of mitochondrial pathologies associated with the decreased levels of mitochondrial proteins.

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