Dose-dependent CHCHD10 dysregulation dictates motor neuron disease severity and alters creatine metabolism
Abstract Dominant defects in CHCHD10, a mitochondrial intermembrane space protein, lead to a range of neurological and muscle disease phenotypes including amyotrophic lateral sclerosis. Many patients present with spinal muscular atrophy Jokela type (SMAJ), which is caused by heterozygous p.G66V vari...
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BMC
2025-05-01
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| Series: | Acta Neuropathologica Communications |
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| Online Access: | https://doi.org/10.1186/s40478-025-02039-3 |
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| author | Sandra Harjuhaahto Manu Jokela Jayasimman Rajendran Minea Rokka Bowen Hu Jouni Kvist Fuping Zhang Tomáš Zárybnický Kimmo Haimilahti Liliya Euro Eija Pirinen Nadine Huber Sanna-Kaisa Herukka Annakaisa Haapasalo Emilia Kuuluvainen Swetha Gopalakrishnan Pekka Katajisto Ville Hietakangas Thibaut Burg Ludo Van Den Bosch Xiaoping Huang Derek P. Narendra Satu Kuure Emil Ylikallio Henna Tyynismaa |
| author_facet | Sandra Harjuhaahto Manu Jokela Jayasimman Rajendran Minea Rokka Bowen Hu Jouni Kvist Fuping Zhang Tomáš Zárybnický Kimmo Haimilahti Liliya Euro Eija Pirinen Nadine Huber Sanna-Kaisa Herukka Annakaisa Haapasalo Emilia Kuuluvainen Swetha Gopalakrishnan Pekka Katajisto Ville Hietakangas Thibaut Burg Ludo Van Den Bosch Xiaoping Huang Derek P. Narendra Satu Kuure Emil Ylikallio Henna Tyynismaa |
| author_sort | Sandra Harjuhaahto |
| collection | DOAJ |
| description | Abstract Dominant defects in CHCHD10, a mitochondrial intermembrane space protein, lead to a range of neurological and muscle disease phenotypes including amyotrophic lateral sclerosis. Many patients present with spinal muscular atrophy Jokela type (SMAJ), which is caused by heterozygous p.G66V variant. While most disease variants lead to aggregation of CHCHD10 and activation of proteotoxic stress responses, the pathogenic mechanisms of the p.G66V variant are less clear. Here we report the first homozygous CHCHD10 patient, and show that the variant dosage dictates the severity of the motor neuron disease in SMAJ. We demonstrate that the amount of the mutant CHCHD10 is reduced, but the disease mechanism of p.G66V is not full haploinsufficiency as residual mutant CHCHD10 protein is present even in a homozygous state. Novel knock-in mouse model recapitulates the dose-dependent reduction of mutant CHCHD10 protein and the slow disease progression of SMAJ. With metabolome analysis of patients’ primary fibroblasts and patient-specific motor neurons, we show that CHCHD10 p.G66V dysregulates energy metabolism, leading to altered redox balance and energy buffering by creatine metabolism. |
| format | Article |
| id | doaj-art-ded76fc87e8449d3931003f247f6e540 |
| institution | OA Journals |
| issn | 2051-5960 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj-art-ded76fc87e8449d3931003f247f6e5402025-08-20T01:53:26ZengBMCActa Neuropathologica Communications2051-59602025-05-0113112110.1186/s40478-025-02039-3Dose-dependent CHCHD10 dysregulation dictates motor neuron disease severity and alters creatine metabolismSandra Harjuhaahto0Manu Jokela1Jayasimman Rajendran2Minea Rokka3Bowen Hu4Jouni Kvist5Fuping Zhang6Tomáš Zárybnický7Kimmo Haimilahti8Liliya Euro9Eija Pirinen10Nadine Huber11Sanna-Kaisa Herukka12Annakaisa Haapasalo13Emilia Kuuluvainen14Swetha Gopalakrishnan15Pekka Katajisto16Ville Hietakangas17Thibaut Burg18Ludo Van Den Bosch19Xiaoping Huang20Derek P. Narendra21Satu Kuure22Emil Ylikallio23Henna Tyynismaa24Stem Cells and Metabolism Research Program, Faculty of Medicine, University of HelsinkiClinical Neurosciences, University of Turku and Neurocenter, and Turku University HospitalStem Cells and Metabolism Research Program, Faculty of Medicine, University of HelsinkiStem Cells and Metabolism Research Program, Faculty of Medicine, University of HelsinkiStem Cells and Metabolism Research Program, Faculty of Medicine, University of HelsinkiStem Cells and Metabolism Research Program, Faculty of Medicine, University of HelsinkiStem Cells and Metabolism Research Program, Faculty of Medicine, University of HelsinkiStem Cells and Metabolism Research Program, Faculty of Medicine, University of HelsinkiResearch Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of HelsinkiStem Cells and Metabolism Research Program, Faculty of Medicine, University of HelsinkiResearch Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of HelsinkiA.I. Virtanen Institute for Molecular Sciences, University of Eastern FinlandDepartment of Neurology, Kuopio University HospitalA.I. Virtanen Institute for Molecular Sciences, University of Eastern FinlandInstitute of Biotechnology, HiLIFE, University of HelsinkiInstitute of Biotechnology, HiLIFE, University of HelsinkiInstitute of Biotechnology, HiLIFE, University of HelsinkiFaculty of Biological and Environmental Sciences, University of HelsinkiDepartment of Neurosciences, Experimental Neurology and Leuven Brain Institute, KU LeuvenDepartment of Neurosciences, Experimental Neurology and Leuven Brain Institute, KU LeuvenMitochondrial Biology and Neurodegeneration Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of HealthMitochondrial Biology and Neurodegeneration Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of HealthStem Cells and Metabolism Research Program, Faculty of Medicine, University of HelsinkiStem Cells and Metabolism Research Program, Faculty of Medicine, University of HelsinkiStem Cells and Metabolism Research Program, Faculty of Medicine, University of HelsinkiAbstract Dominant defects in CHCHD10, a mitochondrial intermembrane space protein, lead to a range of neurological and muscle disease phenotypes including amyotrophic lateral sclerosis. Many patients present with spinal muscular atrophy Jokela type (SMAJ), which is caused by heterozygous p.G66V variant. While most disease variants lead to aggregation of CHCHD10 and activation of proteotoxic stress responses, the pathogenic mechanisms of the p.G66V variant are less clear. Here we report the first homozygous CHCHD10 patient, and show that the variant dosage dictates the severity of the motor neuron disease in SMAJ. We demonstrate that the amount of the mutant CHCHD10 is reduced, but the disease mechanism of p.G66V is not full haploinsufficiency as residual mutant CHCHD10 protein is present even in a homozygous state. Novel knock-in mouse model recapitulates the dose-dependent reduction of mutant CHCHD10 protein and the slow disease progression of SMAJ. With metabolome analysis of patients’ primary fibroblasts and patient-specific motor neurons, we show that CHCHD10 p.G66V dysregulates energy metabolism, leading to altered redox balance and energy buffering by creatine metabolism.https://doi.org/10.1186/s40478-025-02039-3CHCHD10CHCHD2ALSMitochondriaCreatineMetabolomics |
| spellingShingle | Sandra Harjuhaahto Manu Jokela Jayasimman Rajendran Minea Rokka Bowen Hu Jouni Kvist Fuping Zhang Tomáš Zárybnický Kimmo Haimilahti Liliya Euro Eija Pirinen Nadine Huber Sanna-Kaisa Herukka Annakaisa Haapasalo Emilia Kuuluvainen Swetha Gopalakrishnan Pekka Katajisto Ville Hietakangas Thibaut Burg Ludo Van Den Bosch Xiaoping Huang Derek P. Narendra Satu Kuure Emil Ylikallio Henna Tyynismaa Dose-dependent CHCHD10 dysregulation dictates motor neuron disease severity and alters creatine metabolism Acta Neuropathologica Communications CHCHD10 CHCHD2 ALS Mitochondria Creatine Metabolomics |
| title | Dose-dependent CHCHD10 dysregulation dictates motor neuron disease severity and alters creatine metabolism |
| title_full | Dose-dependent CHCHD10 dysregulation dictates motor neuron disease severity and alters creatine metabolism |
| title_fullStr | Dose-dependent CHCHD10 dysregulation dictates motor neuron disease severity and alters creatine metabolism |
| title_full_unstemmed | Dose-dependent CHCHD10 dysregulation dictates motor neuron disease severity and alters creatine metabolism |
| title_short | Dose-dependent CHCHD10 dysregulation dictates motor neuron disease severity and alters creatine metabolism |
| title_sort | dose dependent chchd10 dysregulation dictates motor neuron disease severity and alters creatine metabolism |
| topic | CHCHD10 CHCHD2 ALS Mitochondria Creatine Metabolomics |
| url | https://doi.org/10.1186/s40478-025-02039-3 |
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