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ResearchIn-Press PreviewCell biologyGenetics Open Access | 10.1172/JCI157504

OMA1 mediates local and global stress responses against protein misfolding in CHCHD10 mitochondrial myopathy

Mario K. Shammas,1 Xiaoping Huang,1 Beverly P. Wu,1 Evelyn Fessler,2 Insung Song,1 Nicholas P. Randolph,1 Yan Li,3 Christopher K.E. Bleck,4 Danielle A. Springer,5 Carl Fratter,6 Ines A. Barbosa,7 Andrew F. Powers,8 Pedro M. Quirós,9 Carlos Lopez-Otin,9 Lucas T. Jae,2 Joanna Poulton,10 and Derek P. Narendra1

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 Shammas, M. 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

Find articles by Huang, X. 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

Find articles by Wu, B. 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

Find articles by Fessler, E. 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

Find articles by Song, I. 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

Find articles by Randolph, N. 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

Find articles by Li, Y. 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

Find articles by Bleck, C. 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

Find articles by Springer, D. 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

Find articles by Fratter, C. 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

Find articles by Barbosa, I. 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

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

Find articles by Quirós, P. 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

Find articles by Lopez-Otin, C. 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

Find articles by Jae, L. 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

Find articles by Poulton, J. 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

Find articles by Narendra, D. in: JCI | PubMed | Google Scholar |

Published June 14, 2022 - More info

J Clin Invest. https://doi.org/10.1172/JCI157504.
Copyright © 2022, Shammas et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published June 14, 2022 - Version history
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Abstract

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.

Graphical Abstract
graphical abstract
Supplemental material

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 1: Mitochondrial membrane potential of untreated and DOX (C10 WT or mutant overexpressing)-treated HEK293 cells

View Supplemental Video 2: FIB-SEM segmentation of heart mitochondria

View Supplemental Video 3: Segmented non-megamitochondria (shades of cyan) and megamitochondria (differently colored) from the C10G58R ; OMA1-/- dataset

View

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  • Version 1 (June 14, 2022): In-Press Preview

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