PMID- 30885959
OWN - NLM
STAT- MEDLINE
DCOM- 20200427
LR  - 20230201
IS  - 1757-4684 (Electronic)
IS  - 1757-4676 (Print)
IS  - 1757-4676 (Linking)
VI  - 11
IP  - 5
DP  - 2019 May
TI  - Inhibition of proteasome rescues a pathogenic variant of respiratory chain 
      assembly factor COA7.
LID - 10.15252/emmm.201809561 [doi]
LID - e9561
AB  - 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.
CI  - (c) 2019 The Authors. Published under the terms of the CC BY 4.0 license.
FAU - Mohanraj, Karthik
AU  - Mohanraj K
AD  - Laboratory of Mitochondrial Biogenesis, Centre of New Technologies, University of 
      Warsaw, Warsaw, Poland.
AD  - ReMedy International Research Agenda Unit, Centre of New Technologies, University 
      of Warsaw, Warsaw, Poland.
AD  - Laboratory of Mitochondrial Biogenesis, International Institute of Molecular and 
      Cell Biology, Warsaw, Poland.
FAU - Wasilewski, Michal
AU  - Wasilewski M
AUID- ORCID: 0000-0002-4890-5103
AD  - Laboratory of Mitochondrial Biogenesis, Centre of New Technologies, University of 
      Warsaw, Warsaw, Poland m.wasilewski@cent.uw.edu.pl a.chacinska@cent.uw.edu.pl.
AD  - Laboratory of Mitochondrial Biogenesis, International Institute of Molecular and 
      Cell Biology, Warsaw, Poland.
FAU - Beninca, Cristiane
AU  - Beninca C
AD  - MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
FAU - Cysewski, Dominik
AU  - Cysewski D
AD  - Mass Spectrometry Lab, Department of Biophysics, Institute of Biochemistry and 
      Biophysics, Warsaw, Poland.
FAU - Poznanski, Jaroslaw
AU  - Poznanski J
AD  - Department of Biophysics, Institute of Biochemistry and Biophysics, Warsaw, 
      Poland.
FAU - Sakowska, Paulina
AU  - Sakowska P
AD  - Laboratory of Mitochondrial Biogenesis, International Institute of Molecular and 
      Cell Biology, Warsaw, Poland.
FAU - Bugajska, Zaneta
AU  - Bugajska Z
AD  - Laboratory of Mitochondrial Biogenesis, Centre of New Technologies, University of 
      Warsaw, Warsaw, Poland.
FAU - Deckers, Markus
AU  - Deckers M
AD  - Department of Cellular Biochemistry, University of Gottingen, Gottingen, Germany.
FAU - Dennerlein, Sven
AU  - Dennerlein S
AD  - Department of Cellular Biochemistry, University of Gottingen, Gottingen, Germany.
FAU - Fernandez-Vizarra, Erika
AU  - Fernandez-Vizarra E
AUID- ORCID: 0000-0002-2469-142X
AD  - MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
FAU - Rehling, Peter
AU  - Rehling P
AD  - Department of Cellular Biochemistry, University of Gottingen, Gottingen, Germany.
AD  - Max Planck Institute for Biophysical Chemistry, Gottingen, Germany.
FAU - Dadlez, Michal
AU  - Dadlez M
AD  - Mass Spectrometry Lab, Department of Biophysics, Institute of Biochemistry and 
      Biophysics, Warsaw, Poland.
FAU - Zeviani, Massimo
AU  - Zeviani M
AUID- ORCID: 0000-0002-9067-5508
AD  - MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
FAU - Chacinska, Agnieszka
AU  - Chacinska A
AUID- ORCID: 0000-0002-2832-2568
AD  - Laboratory of Mitochondrial Biogenesis, Centre of New Technologies, University of 
      Warsaw, Warsaw, Poland m.wasilewski@cent.uw.edu.pl a.chacinska@cent.uw.edu.pl.
AD  - ReMedy International Research Agenda Unit, Centre of New Technologies, University 
      of Warsaw, Warsaw, Poland.
AD  - Laboratory of Mitochondrial Biogenesis, International Institute of Molecular and 
      Cell Biology, Warsaw, Poland.
LA  - eng
GR  - MC_UP_1002/1/MRC_/Medical Research Council/United Kingdom
GR  - MC_UU_00015/5/MRC_/Medical Research Council/United Kingdom
GR  - MC_UU_00015/8/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Germany
TA  - EMBO Mol Med
JT  - EMBO molecular medicine
JID - 101487380
RN  - 0 (CHCHD4 protein, human)
RN  - 0 (COA7 protein, human)
RN  - 0 (Disulfides)
RN  - 0 (Mitochondrial Membrane Transport Proteins)
RN  - 0 (Mitochondrial Precursor Protein Import Complex Proteins)
RN  - 0 (Mitochondrial Proteins)
RN  - 0 (Mutant Proteins)
RN  - 0 (Proteasome Inhibitors)
RN  - 0 (Ubiquitin)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
SB  - IM
MH  - Cytosol/drug effects/metabolism
MH  - Disulfides/metabolism
MH  - Electron Transport/drug effects
MH  - Fibroblasts/drug effects/metabolism
MH  - HEK293 Cells
MH  - HeLa Cells
MH  - Humans
MH  - Mitochondria/drug effects/metabolism
MH  - Mitochondrial Membrane Transport Proteins/metabolism
MH  - Mitochondrial Membranes/drug effects/metabolism
MH  - Mitochondrial Precursor Protein Import Complex Proteins
MH  - Mitochondrial Proteins/*metabolism
MH  - Mutant Proteins/metabolism
MH  - Mutation/*genetics
MH  - Oxidation-Reduction/drug effects
MH  - Proteasome Endopeptidase Complex/*metabolism
MH  - Proteasome Inhibitors/*pharmacology
MH  - Protein Binding/drug effects
MH  - Protein Transport/drug effects
MH  - Ubiquitin/metabolism
PMC - PMC6505684
OTO - NOTNLM
OT  - COA7/RESA1
OT  - mitochondrial disease
OT  - proteasome
OT  - protein degradation
OT  - protein import
COIS- The authors declare that they have no conflict of interest.
EDAT- 2019/03/20 06:00
MHDA- 2020/04/28 06:00
PMCR- 2019/05/01
CRDT- 2019/03/20 06:00
PHST- 2019/03/20 06:00 [pubmed]
PHST- 2020/04/28 06:00 [medline]
PHST- 2019/03/20 06:00 [entrez]
PHST- 2019/05/01 00:00 [pmc-release]
AID - emmm.201809561 [pii]
AID - EMMM201809561 [pii]
AID - 10.15252/emmm.201809561 [doi]
PST - ppublish
SO  - EMBO Mol Med. 2019 May;11(5):e9561. doi: 10.15252/emmm.201809561.