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ResearchIn-Press PreviewCell biologyGenetics
Open Access | 10.1172/JCI157504
1Inherited Movement Disorders Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, United States of America
2Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
3Proteomics Core Facility, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States of America
4Electron Microscopy Core Facility, National Heart, Lung, and Blood Institute, Bethesda, United States of America
5Mouse Phenotyping Core, National Heart, Lung, and Blood Institute, Bethesda, United States of America
6Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
7Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
8Ionis Pharmaceuticals, Carlsbad, United States of America
9Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, Oviedo, Spain
10Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, United Kingdom
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Shammas, M.
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1Inherited Movement Disorders Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, United States of America
2Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
3Proteomics Core Facility, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States of America
4Electron Microscopy Core Facility, National Heart, Lung, and Blood Institute, Bethesda, United States of America
5Mouse Phenotyping Core, National Heart, Lung, and Blood Institute, Bethesda, United States of America
6Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
7Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
8Ionis Pharmaceuticals, Carlsbad, United States of America
9Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, Oviedo, Spain
10Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, United Kingdom
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1Inherited Movement Disorders Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, United States of America
2Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
3Proteomics Core Facility, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States of America
4Electron Microscopy Core Facility, National Heart, Lung, and Blood Institute, Bethesda, United States of America
5Mouse Phenotyping Core, National Heart, Lung, and Blood Institute, Bethesda, United States of America
6Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
7Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
8Ionis Pharmaceuticals, Carlsbad, United States of America
9Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, Oviedo, Spain
10Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, United Kingdom
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1Inherited Movement Disorders Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, United States of America
2Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
3Proteomics Core Facility, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States of America
4Electron Microscopy Core Facility, National Heart, Lung, and Blood Institute, Bethesda, United States of America
5Mouse Phenotyping Core, National Heart, Lung, and Blood Institute, Bethesda, United States of America
6Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
7Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
8Ionis Pharmaceuticals, Carlsbad, United States of America
9Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, Oviedo, Spain
10Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, United Kingdom
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Fessler, E.
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1Inherited Movement Disorders Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, United States of America
2Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
3Proteomics Core Facility, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States of America
4Electron Microscopy Core Facility, National Heart, Lung, and Blood Institute, Bethesda, United States of America
5Mouse Phenotyping Core, National Heart, Lung, and Blood Institute, Bethesda, United States of America
6Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
7Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
8Ionis Pharmaceuticals, Carlsbad, United States of America
9Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, Oviedo, Spain
10Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, United Kingdom
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1Inherited Movement Disorders Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, United States of America
2Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
3Proteomics Core Facility, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States of America
4Electron Microscopy Core Facility, National Heart, Lung, and Blood Institute, Bethesda, United States of America
5Mouse Phenotyping Core, National Heart, Lung, and Blood Institute, Bethesda, United States of America
6Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
7Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
8Ionis Pharmaceuticals, Carlsbad, United States of America
9Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, Oviedo, Spain
10Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, United Kingdom
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Randolph, N.
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1Inherited Movement Disorders Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, United States of America
2Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
3Proteomics Core Facility, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States of America
4Electron Microscopy Core Facility, National Heart, Lung, and Blood Institute, Bethesda, United States of America
5Mouse Phenotyping Core, National Heart, Lung, and Blood Institute, Bethesda, United States of America
6Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
7Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
8Ionis Pharmaceuticals, Carlsbad, United States of America
9Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, Oviedo, Spain
10Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, United Kingdom
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Li, Y.
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1Inherited Movement Disorders Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, United States of America
2Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
3Proteomics Core Facility, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States of America
4Electron Microscopy Core Facility, National Heart, Lung, and Blood Institute, Bethesda, United States of America
5Mouse Phenotyping Core, National Heart, Lung, and Blood Institute, Bethesda, United States of America
6Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
7Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
8Ionis Pharmaceuticals, Carlsbad, United States of America
9Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, Oviedo, Spain
10Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, United Kingdom
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Bleck, C.
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1Inherited Movement Disorders Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, United States of America
2Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
3Proteomics Core Facility, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States of America
4Electron Microscopy Core Facility, National Heart, Lung, and Blood Institute, Bethesda, United States of America
5Mouse Phenotyping Core, National Heart, Lung, and Blood Institute, Bethesda, United States of America
6Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
7Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
8Ionis Pharmaceuticals, Carlsbad, United States of America
9Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, Oviedo, Spain
10Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, United Kingdom
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1Inherited Movement Disorders Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, United States of America
2Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
3Proteomics Core Facility, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States of America
4Electron Microscopy Core Facility, National Heart, Lung, and Blood Institute, Bethesda, United States of America
5Mouse Phenotyping Core, National Heart, Lung, and Blood Institute, Bethesda, United States of America
6Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
7Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
8Ionis Pharmaceuticals, Carlsbad, United States of America
9Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, Oviedo, Spain
10Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, United Kingdom
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Fratter, C.
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1Inherited Movement Disorders Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, United States of America
2Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
3Proteomics Core Facility, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States of America
4Electron Microscopy Core Facility, National Heart, Lung, and Blood Institute, Bethesda, United States of America
5Mouse Phenotyping Core, National Heart, Lung, and Blood Institute, Bethesda, United States of America
6Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
7Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
8Ionis Pharmaceuticals, Carlsbad, United States of America
9Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, Oviedo, Spain
10Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, United Kingdom
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1Inherited Movement Disorders Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, United States of America
2Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
3Proteomics Core Facility, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States of America
4Electron Microscopy Core Facility, National Heart, Lung, and Blood Institute, Bethesda, United States of America
5Mouse Phenotyping Core, National Heart, Lung, and Blood Institute, Bethesda, United States of America
6Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
7Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
8Ionis Pharmaceuticals, Carlsbad, United States of America
9Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, Oviedo, Spain
10Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, United Kingdom
Find articles by Powers, A. in: JCI | PubMed | Google Scholar
1Inherited Movement Disorders Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, United States of America
2Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
3Proteomics Core Facility, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States of America
4Electron Microscopy Core Facility, National Heart, Lung, and Blood Institute, Bethesda, United States of America
5Mouse Phenotyping Core, National Heart, Lung, and Blood Institute, Bethesda, United States of America
6Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
7Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
8Ionis Pharmaceuticals, Carlsbad, United States of America
9Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, Oviedo, Spain
10Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, United Kingdom
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Quirós, P.
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1Inherited Movement Disorders Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, United States of America
2Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
3Proteomics Core Facility, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States of America
4Electron Microscopy Core Facility, National Heart, Lung, and Blood Institute, Bethesda, United States of America
5Mouse Phenotyping Core, National Heart, Lung, and Blood Institute, Bethesda, United States of America
6Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
7Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
8Ionis Pharmaceuticals, Carlsbad, United States of America
9Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, Oviedo, Spain
10Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, United Kingdom
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1Inherited Movement Disorders Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, United States of America
2Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
3Proteomics Core Facility, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States of America
4Electron Microscopy Core Facility, National Heart, Lung, and Blood Institute, Bethesda, United States of America
5Mouse Phenotyping Core, National Heart, Lung, and Blood Institute, Bethesda, United States of America
6Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
7Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
8Ionis Pharmaceuticals, Carlsbad, United States of America
9Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, Oviedo, Spain
10Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, United Kingdom
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Jae, L.
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1Inherited Movement Disorders Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, United States of America
2Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
3Proteomics Core Facility, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States of America
4Electron Microscopy Core Facility, National Heart, Lung, and Blood Institute, Bethesda, United States of America
5Mouse Phenotyping Core, National Heart, Lung, and Blood Institute, Bethesda, United States of America
6Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
7Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
8Ionis Pharmaceuticals, Carlsbad, United States of America
9Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, Oviedo, Spain
10Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, United Kingdom
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Poulton, J.
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1Inherited Movement Disorders Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, United States of America
2Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
3Proteomics Core Facility, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States of America
4Electron Microscopy Core Facility, National Heart, Lung, and Blood Institute, Bethesda, United States of America
5Mouse Phenotyping Core, National Heart, Lung, and Blood Institute, Bethesda, United States of America
6Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
7Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
8Ionis Pharmaceuticals, Carlsbad, United States of America
9Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, Oviedo, Spain
10Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, United Kingdom
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Narendra, D.
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Published June 14, 2022 - More info
Mitochondrial stress triggers a response in the cell’s mitochondria and nucleus, but how these stress responses are coordinated in vivo is poorly understood. Here, we characterize a family with myopathy caused by a dominant p.G58R mutation in the mitochondrial protein CHCHD10. To understand the disease etiology, we developed a knock-in mouse model and found that mutant CHCHD10 aggregates in affected tissues, applying a toxic protein stress to the inner mitochondrial membrane. Unexpectedly, survival of CHCHD10 knock-in mice depended on a protective stress response mediated by OMA1. The OMA1 stress response acted both locally within mitochondria, causing mitochondrial fragmentation, and signaled outside the mitochondria, activating the integrated stress response through cleavage of DELE1. We additionally identified an isoform switch in the terminal complex of the electron transport chain as a component of this response. Our results demonstrate that OMA1 is critical for neonatal survival conditionally in the setting of inner mitochondrial membrane stress, coordinating local and global stress responses to reshape the mitochondrial network and proteome.
View Supplemental File 1: Echocardiography of mouse hearts
View Supplemental File 2: Proteomics of HEK293 dox-inducible cells and mouse hearts
View Supplemental File 3: Gene expression foldchanges of mouse hearts
View Supplemental File 4: Gene set enrichment analyses of gene expression data
View Supplemental Video 2: FIB-SEM segmentation of heart mitochondria