Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7
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 mit...
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| Format: | Article |
| Language: | English |
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Springer Nature
2019-03-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201809561 |
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| author | Karthik Mohanraj Michal Wasilewski Cristiane Benincá Dominik Cysewski Jaroslaw Poznanski Paulina Sakowska Zaneta Bugajska Markus Deckers Sven Dennerlein Erika Fernandez‐Vizarra Peter Rehling Michal Dadlez Massimo Zeviani Agnieszka Chacinska |
| author_facet | Karthik Mohanraj Michal Wasilewski Cristiane Benincá Dominik Cysewski Jaroslaw Poznanski Paulina Sakowska Zaneta Bugajska Markus Deckers Sven Dennerlein Erika Fernandez‐Vizarra Peter Rehling Michal Dadlez Massimo Zeviani Agnieszka Chacinska |
| author_sort | Karthik Mohanraj |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-03dc98b418614bc6bc41907e2c528d8b |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2019-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-03dc98b418614bc6bc41907e2c528d8b2025-08-20T03:06:00ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842019-03-0111512110.15252/emmm.201809561Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7Karthik Mohanraj0Michal Wasilewski1Cristiane Benincá2Dominik Cysewski3Jaroslaw Poznanski4Paulina Sakowska5Zaneta Bugajska6Markus Deckers7Sven Dennerlein8Erika Fernandez‐Vizarra9Peter Rehling10Michal Dadlez11Massimo Zeviani12Agnieszka Chacinska13Laboratory of Mitochondrial Biogenesis, Centre of New Technologies, University of WarsawLaboratory of Mitochondrial Biogenesis, Centre of New Technologies, University of WarsawMRC Mitochondrial Biology Unit, University of CambridgeMass Spectrometry Lab, Department of Biophysics, Institute of Biochemistry and BiophysicsDepartment of Biophysics, Institute of Biochemistry and BiophysicsLaboratory of Mitochondrial Biogenesis, International Institute of Molecular and Cell BiologyLaboratory of Mitochondrial Biogenesis, Centre of New Technologies, University of WarsawDepartment of Cellular Biochemistry, University of GöttingenDepartment of Cellular Biochemistry, University of GöttingenMRC Mitochondrial Biology Unit, University of CambridgeDepartment of Cellular Biochemistry, University of GöttingenMass Spectrometry Lab, Department of Biophysics, Institute of Biochemistry and BiophysicsMRC Mitochondrial Biology Unit, University of CambridgeLaboratory of Mitochondrial Biogenesis, Centre of New Technologies, University of WarsawAbstract 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.https://doi.org/10.15252/emmm.201809561COA7/RESA1mitochondrial diseaseproteasomeprotein degradationprotein import |
| spellingShingle | Karthik Mohanraj Michal Wasilewski Cristiane Benincá Dominik Cysewski Jaroslaw Poznanski Paulina Sakowska Zaneta Bugajska Markus Deckers Sven Dennerlein Erika Fernandez‐Vizarra Peter Rehling Michal Dadlez Massimo Zeviani Agnieszka Chacinska Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7 EMBO Molecular Medicine COA7/RESA1 mitochondrial disease proteasome protein degradation protein import |
| title | Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7 |
| title_full | Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7 |
| title_fullStr | Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7 |
| title_full_unstemmed | Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7 |
| title_short | Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7 |
| title_sort | inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor coa7 |
| topic | COA7/RESA1 mitochondrial disease proteasome protein degradation protein import |
| url | https://doi.org/10.15252/emmm.201809561 |
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