A novel CHCHD10 mutation implicates a Mia40‐dependent mitochondrial import deficit in ALS
Abstract 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 aggres...
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| Format: | Article |
| Language: | English |
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Springer Nature
2018-05-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201708558 |
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| _version_ | 1849234575094448128 |
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| author | Carina Lehmer Martin H Schludi Linnea Ransom Johanna Greiling Michaela Junghänel Nicole Exner Henrick Riemenschneider Julie van der Zee Christine Van Broeckhoven Patrick Weydt Michael T Heneka Dieter Edbauer |
| author_facet | Carina Lehmer Martin H Schludi Linnea Ransom Johanna Greiling Michaela Junghänel Nicole Exner Henrick Riemenschneider Julie van der Zee Christine Van Broeckhoven Patrick Weydt Michael T Heneka Dieter Edbauer |
| author_sort | Carina Lehmer |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-e5c50d6c5b4645e99a546abfbbb506e9 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2018-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-e5c50d6c5b4645e99a546abfbbb506e92025-08-20T04:03:06ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842018-05-0110611410.15252/emmm.201708558A novel CHCHD10 mutation implicates a Mia40‐dependent mitochondrial import deficit in ALSCarina Lehmer0Martin H Schludi1Linnea Ransom2Johanna Greiling3Michaela Junghänel4Nicole Exner5Henrick Riemenschneider6Julie van der Zee7Christine Van Broeckhoven8Patrick Weydt9Michael T Heneka10Dieter Edbauer11German Center for Neurodegenerative Diseases (DZNE) MunichGerman Center for Neurodegenerative Diseases (DZNE) MunichGerman Center for Neurodegenerative Diseases (DZNE) MunichGerman Center for Neurodegenerative Diseases (DZNE) MunichGerman Center for Neurodegenerative Diseases (DZNE) MunichBiomedical Center (BMC), Biochemistry, Ludwig‐Maximilians‐Universität MünchenGerman Center for Neurodegenerative Diseases (DZNE) MunichNeurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIBNeurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIBDepartment of Neurodegenerative Diseases and Geriatric Psychiatry, Bonn University HospitalDepartment of Neurodegenerative Diseases and Geriatric Psychiatry, Bonn University HospitalGerman Center for Neurodegenerative Diseases (DZNE) MunichAbstract 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.https://doi.org/10.15252/emmm.201708558amyotrophic lateral sclerosisCHCHD10geneticsmitochondria |
| spellingShingle | Carina Lehmer Martin H Schludi Linnea Ransom Johanna Greiling Michaela Junghänel Nicole Exner Henrick Riemenschneider Julie van der Zee Christine Van Broeckhoven Patrick Weydt Michael T Heneka Dieter Edbauer A novel CHCHD10 mutation implicates a Mia40‐dependent mitochondrial import deficit in ALS EMBO Molecular Medicine amyotrophic lateral sclerosis CHCHD10 genetics mitochondria |
| title | A novel CHCHD10 mutation implicates a Mia40‐dependent mitochondrial import deficit in ALS |
| title_full | A novel CHCHD10 mutation implicates a Mia40‐dependent mitochondrial import deficit in ALS |
| title_fullStr | A novel CHCHD10 mutation implicates a Mia40‐dependent mitochondrial import deficit in ALS |
| title_full_unstemmed | A novel CHCHD10 mutation implicates a Mia40‐dependent mitochondrial import deficit in ALS |
| title_short | A novel CHCHD10 mutation implicates a Mia40‐dependent mitochondrial import deficit in ALS |
| title_sort | novel chchd10 mutation implicates a mia40 dependent mitochondrial import deficit in als |
| topic | amyotrophic lateral sclerosis CHCHD10 genetics mitochondria |
| url | https://doi.org/10.15252/emmm.201708558 |
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