2. Academic Validation
  3. Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7

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

  • EMBO Mol Med. 2019 May;11(5):e9561. doi: 10.15252/emmm.201809561.
Karthik Mohanraj 1 2 3,  Michal Wasilewski 4 3,  Cristiane Benincá 5,  Dominik Cysewski 6,  Jaroslaw Poznanski 7,  Paulina Sakowska 3,  Zaneta Bugajska 1,  Markus Deckers 8,  Sven Dennerlein 8,  Erika Fernandez-Vizarra 5,  Peter Rehling 8 9,  Michal Dadlez 6,  Massimo Zeviani 5,  Agnieszka Chacinska 4 2 3
Affiliations

Affiliations

  • 1 Laboratory of Mitochondrial Biogenesis, Centre of New Technologies, University of Warsaw, Warsaw, Poland.
  • 2 ReMedy International Research Agenda Unit, Centre of New Technologies, University of Warsaw, Warsaw, Poland.
  • 3 Laboratory of Mitochondrial Biogenesis, International Institute of Molecular and Cell Biology, Warsaw, Poland.
  • 4 Laboratory of Mitochondrial Biogenesis, Centre of New Technologies, University of Warsaw, Warsaw, Poland [email protected] [email protected].
  • 5 MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
  • 6 Mass Spectrometry Lab, Department of Biophysics, Institute of Biochemistry and Biophysics, Warsaw, Poland.
  • 7 Department of Biophysics, Institute of Biochemistry and Biophysics, Warsaw, Poland.
  • 8 Department of Cellular Biochemistry, University of Göttingen, Göttingen, Germany.
  • 9 Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
PMID: 30885959 DOI: 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.

Keywords

COA7/RESA1; mitochondrial disease; proteasome; protein degradation; protein import.

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