CHCHD10; amyotrophic lateral sclerosis; genetics; mitochondria; CHCHD10 protein, human; CHCHD4 protein, human; Mitochondrial Membrane Transport Proteins; Mitochondrial Precursor Protein Import Complex Proteins; Mitochondrial Proteins; Adult; Amyotrophic Lateral Sclerosis/genetics; Cell Respiration/genetics; Clustered Regularly Interspaced Short Palindromic Repeats; Genetic Association Studies; HeLa Cells; Humans; Mitochondria/metabolism; Mitochondrial Membrane Transport Proteins/genetics; Mitochondrial Membrane Transport Proteins/metabolism; Mitochondrial Membrane Transport Proteins/physiology; Mitochondrial Proteins/genetics; RNA Interference; Cell Respiration; Molecular Medicine
Résumé :
[en] CHCHD10 mutations are linked to amyotrophic lateral sclerosis, but their mode of action is unclear. In a 29-year-old patient with rapid disease progression, we discovered a novel mutation (Q108P) in a conserved residue within the coiled-coil-helix-coiled-coil-helix (CHCH) domain. The aggressive clinical phenotype prompted us to probe its pathogenicity. Unlike the wild-type protein, mitochondrial import of CHCHD10 Q108P was blocked nearly completely resulting in diffuse cytoplasmic localization and reduced stability. Other CHCHD10 variants reported in patients showed impaired mitochondrial import (C122R) or clustering within mitochondria (especially G66V and E127K) often associated with reduced expression. Truncation experiments suggest mitochondrial import of CHCHD10 is mediated by the CHCH domain rather than the proposed N-terminal mitochondrial targeting signal. Knockdown of Mia40, which introduces disulfide bonds into CHCH domain proteins, blocked mitochondrial import of CHCHD10. Overexpression of Mia40 rescued mitochondrial import of CHCHD10 Q108P by enhancing disulfide-bond formation. Since reduction in CHCHD10 inhibits respiration, mutations in its CHCH domain may cause aggressive disease by impairing mitochondrial import. Our data suggest Mia40 upregulation as a potential therapeutic salvage pathway.
Disciplines :
Neurologie
Auteur, co-auteur :
Lehmer, Carina; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany
Schludi, Martin H; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany ; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
Ransom, Linnea; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany
Greiling, Johanna; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany
Junghänel, Michaela; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany
Exner, Nicole; Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
Riemenschneider, Henrick; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany
van der Zee, Julie; Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium ; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Van Broeckhoven, Christine; Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium ; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Weydt, Patrick; Department of Neurodegenerative Diseases and Geriatric Psychiatry, Bonn University Hospital, Bonn, Germany
HENEKA, Michael ; Department of Neurodegenerative Diseases and Geriatric Psychiatry, Bonn University Hospital, Bonn, Germany ; German Center for Neurodegenerative Disease (DZNE) Bonn, Bonn, Germany
Edbauer, Dieter ; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany dieter.edbauer@dzne.de ; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
Co-auteurs externes :
yes
Langue du document :
Anglais
Titre :
A novel CHCHD10 mutation implicates a Mia40-dependent mitochondrial import deficit in ALS.
We thank Hannelore Hartmann, Bettina Schmid, Harald Steiner, Johannes Trambauer, Matias Wagner, and Qihui Zhou for critical comments to the manuscript. This work was supported by NOMIS Foundation and the Hans und Ilse Breuer Foundation (D.E.), the Munich Cluster of Systems Neurology (SyNergy) (D.E.), the European Community’s Health Seventh Framework Programme under Grant agreement no. 617198 [DPR-MODELS] (D.E.) and the general legacy of Mrs. Ammer (N.E.).We thank Hannelore Hartmann, Bettina Schmid, Harald Steiner, Johannes Trambauer, Matias Wagner, and Qihui Zhou for critical comments to the manuscript. This work was supported by NOMIS Foundation and the Hans und Ilse Breuer Foundation (D.E.), the Munich Cluster of Systems Neurology (SyNergy) (D.E.), the European Community's Health Seventh Framework Programme under Grant agreement no. 617198 [DPR-MODELS] (D.E.) and the general legacy of Mrs. Ammer (N.E.).
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