Loss of MICOS complex integrity and mitochondrial damage, but not TDP-43 mitochondrial localisation, are likely associated with severity of CHCHD10-related diseases
| Autor: | Emil Ylikallio, Mari Auranen, Charlotte Cochaud, Jean-Ehrland Ricci, Alessandra Mauri-Crouzet, Henna Tyynismaa, Anna Vihola, Bjarne Udd, Véronique Paquis-Flucklinger, Cristofol Vives-Bauza, Bernardo Ortega-Vila, Gaëlle Augé, Emmanuelle Génin, Manu Jokela, Konstantina Fragaki, Françoise Lespinasse, Sandra Lacas-Gervais, Hiromi Sesaki, Sylvie Bannwarth, Kie Itoh, Elodie Villa |
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| Přispěvatelé: | CCMA - Centre Commun de Microscopie Appliquée, Université Nice Côte D'Azur, Research Programs Unit, Clinicum, Department of Neurosciences, Neurologian yksikkö, University of Helsinki, Research Programme for Molecular Neurology, Centre of Excellence in Stem Cell Metabolism, Medicum, Doctoral Programme Brain & Mind, Henna Tyynismaa / Principal Investigator, Department of Medical and Clinical Genetics, Doctoral Programme in Integrative Life Science, HUS Neurocenter |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Mitochondrial Diseases TDP-43 [SDV]Life Sciences [q-bio] Mitochondrion medicine.disease_cause Severity of Illness Index AMYOTROPHIC-LATERAL-SCLEROSIS 3124 Neurology and psychiatry 0302 clinical medicine Mitochondrial myopathy MOTOR-NEURON DISEASE ComputingMilieux_MISCELLANEOUS Mutation MICOS complex Neurodegeneration NEURODEGENERATION Middle Aged Mitochondria Cell biology DNA-Binding Proteins Neurology Frontotemporal Dementia Female Adult Mitochondrial DNA Saccharomyces cerevisiae Proteins Biology PATIENT Article lcsh:RC321-571 Mitochondrial Proteins 03 medical and health sciences medicine Humans Allele lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry FRONTOTEMPORAL LOBAR DEGENERATION HEXANUCLEOTIDE REPEAT Amyotrophic Lateral Sclerosis 3112 Neurosciences Membrane Proteins Spinal muscular atrophy medicine.disease ta3124 INDIVIDUALS CHCHD10 MUTATIONS HEK293 Cells CHCHD10 030104 developmental biology SMAJ CELLS FTD-ALS ALS 030217 neurology & neurosurgery HeLa Cells |
| Zdroj: | Neurobiology of Disease Neurobiology of Disease, Elsevier, 2018, 119, pp.159-171. ⟨10.1016/j.nbd.2018.07.027⟩ Neurobiology of Disease, Vol 119, Iss, Pp 159-171 (2018) |
| ISSN: | 0969-9961 1095-953X |
| DOI: | 10.1016/j.nbd.2018.07.027⟩ |
| Popis: | Following the involvement of CHCHD10 in FrontoTemporal-Dementia-Amyotrophic Lateral Sclerosis (FTD-ALS) clinical spectrum, a founder mutation (p.Gly66Val) in the same gene was identified in Finnish families with late onset spinal motor neuronopathy (SMAJ). SMAJ is a slowly progressive form of spinal muscular atrophy with a life expectancy within normal range. In order to understand why the p.Ser59Leu mutation, responsible for severe FTD-ALS, and the p.Gly66Val mutation could lead to different levels of severity, we compared their effects in patient cells. Unlike affected individuals bearing the p.Ser59Leu mutation, patients presenting with SMAJ phenotype have neither mitochondrial myopathy nor mtDNA instability. The expression of CHCHD10(S59L) mutant allele leads to disassembly of mitochondrial contact site and cristae organizing system (MICOS) with mitochondria] dysfunction and loss of cristae in patient fibroblasts. We also show that G66V fibroblasts do not display the loss of MICOS complex integrity and mitochondrial damage found in S59L cells. However, S59L and G66V fibroblasts show comparable accumulation of phosphorylated mitochondrial TDP-43 suggesting that the severity of phenotype and mitochondrial damage do not depend on mitochondrial TDP-43 localization. The expression of the CHCHD10(G66V) allele is responsible for mitochondrial network fragmentation and decreased sensitivity towards apoptotic stimuli, but with a less severe effect than that found in cells expressing the CHCHD10(S59L) allele. Taken together, our data show that cellular phenotypes associated with p.Ser59Leu and p.Gly66Val mutations in CHCHD10 are different; loss of MICOS complex integrity and mitochondrial dysfunction, but not TDP-43 mitochondrial localization, being likely essential to develop a severe motor neuron disease. |
| Databáze: | OpenAIRE |
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