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

Mario K. Shammas; Xiaoping Huang; Beverly P. Wu; Evelyn Fessler; Insung Song; Nicholas P. Randolph; Yan Li; Christopher K.E. Bleck; Danielle A. Springer; Carl Fratter; Ines A. Barbosa; Andrew F. Powers; Pedro M. Quirós; Carlos Lopez-Otin; Lucas T. Jae; Joanna Poulton; Derek P. Narendra

doi: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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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 |

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.

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

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

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