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Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7

Mohanraj, Karthik and Wasilewski, Michal and Benincá, Cristiane and Cysewski, Dominik and Poznański, Jarosław and Sakowska, Paulina and Bugajska, Zaneta and Deckers, Markus and Dennerlein, Sven and Fernandez‐Vizarra, Erika and Rehling, Peter and Dadlez, Michal and Zeviani, Massimo and Chacinska, Agnieszka (2019) Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7. EMBO Molecular Medicine, 11 (5). e9561. ISSN 1757-4684

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Official URL: http://doi.org/10.15252/emmm.201809561

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 c 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.

Item Type:Article
Subjects:Q Science > Q Science (General)
R Medicine > R Medicine (General)
Divisions:Department of Biophysics
ID Code:1724
Deposited By: Prof Jaroslaw Poznanski
Deposited On:04 Jun 2019 07:35
Last Modified:04 Jun 2019 07:35

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