Loss of MICOS complex integrity and mitochondrial damage, but not TDP-43 mitochondrial localisation, are likely associated with severity of CHCHD10-related diseases
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...
Main Authors: | , , , , , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2018-11-01
|
Series: | Neurobiology of Disease |
Subjects: | |
Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996118303486 |
id |
doaj-4dd012f21baf4cd2b4f522f52e36c6f3 |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Emmanuelle C. Genin Sylvie Bannwarth Françoise Lespinasse Bernardo Ortega-Vila Konstantina Fragaki Kie Itoh Elodie Villa Sandra Lacas-Gervais Manu Jokela Mari Auranen Emil Ylikallio Alessandra Mauri-Crouzet Henna Tyynismaa Anna Vihola Gaelle Augé Charlotte Cochaud Hiromi Sesaki Jean-Ehrland Ricci Bjarne Udd Cristofol Vives-Bauza Véronique Paquis-Flucklinger |
spellingShingle |
Emmanuelle C. Genin Sylvie Bannwarth Françoise Lespinasse Bernardo Ortega-Vila Konstantina Fragaki Kie Itoh Elodie Villa Sandra Lacas-Gervais Manu Jokela Mari Auranen Emil Ylikallio Alessandra Mauri-Crouzet Henna Tyynismaa Anna Vihola Gaelle Augé Charlotte Cochaud Hiromi Sesaki Jean-Ehrland Ricci Bjarne Udd Cristofol Vives-Bauza Véronique Paquis-Flucklinger Loss of MICOS complex integrity and mitochondrial damage, but not TDP-43 mitochondrial localisation, are likely associated with severity of CHCHD10-related diseases Neurobiology of Disease CHCHD10 SMAJ FTD-ALS Mitochondria TDP-43 |
author_facet |
Emmanuelle C. Genin Sylvie Bannwarth Françoise Lespinasse Bernardo Ortega-Vila Konstantina Fragaki Kie Itoh Elodie Villa Sandra Lacas-Gervais Manu Jokela Mari Auranen Emil Ylikallio Alessandra Mauri-Crouzet Henna Tyynismaa Anna Vihola Gaelle Augé Charlotte Cochaud Hiromi Sesaki Jean-Ehrland Ricci Bjarne Udd Cristofol Vives-Bauza Véronique Paquis-Flucklinger |
author_sort |
Emmanuelle C. Genin |
title |
Loss of MICOS complex integrity and mitochondrial damage, but not TDP-43 mitochondrial localisation, are likely associated with severity of CHCHD10-related diseases |
title_short |
Loss of MICOS complex integrity and mitochondrial damage, but not TDP-43 mitochondrial localisation, are likely associated with severity of CHCHD10-related diseases |
title_full |
Loss of MICOS complex integrity and mitochondrial damage, but not TDP-43 mitochondrial localisation, are likely associated with severity of CHCHD10-related diseases |
title_fullStr |
Loss of MICOS complex integrity and mitochondrial damage, but not TDP-43 mitochondrial localisation, are likely associated with severity of CHCHD10-related diseases |
title_full_unstemmed |
Loss of MICOS complex integrity and mitochondrial damage, but not TDP-43 mitochondrial localisation, are likely associated with severity of CHCHD10-related diseases |
title_sort |
loss of micos complex integrity and mitochondrial damage, but not tdp-43 mitochondrial localisation, are likely associated with severity of chchd10-related diseases |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2018-11-01 |
description |
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 CHCHD10S59L mutant allele leads to disassembly of mitochondrial contact site and cristae organizing system (MICOS) with mitochondrial 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 CHCHD10G66V 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 CHCHD10S59L 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. |
topic |
CHCHD10 SMAJ FTD-ALS Mitochondria TDP-43 |
url |
http://www.sciencedirect.com/science/article/pii/S0969996118303486 |
work_keys_str_mv |
AT emmanuellecgenin lossofmicoscomplexintegrityandmitochondrialdamagebutnottdp43mitochondriallocalisationarelikelyassociatedwithseverityofchchd10relateddiseases AT sylviebannwarth lossofmicoscomplexintegrityandmitochondrialdamagebutnottdp43mitochondriallocalisationarelikelyassociatedwithseverityofchchd10relateddiseases AT francoiselespinasse lossofmicoscomplexintegrityandmitochondrialdamagebutnottdp43mitochondriallocalisationarelikelyassociatedwithseverityofchchd10relateddiseases AT bernardoortegavila lossofmicoscomplexintegrityandmitochondrialdamagebutnottdp43mitochondriallocalisationarelikelyassociatedwithseverityofchchd10relateddiseases AT konstantinafragaki lossofmicoscomplexintegrityandmitochondrialdamagebutnottdp43mitochondriallocalisationarelikelyassociatedwithseverityofchchd10relateddiseases AT kieitoh lossofmicoscomplexintegrityandmitochondrialdamagebutnottdp43mitochondriallocalisationarelikelyassociatedwithseverityofchchd10relateddiseases AT elodievilla lossofmicoscomplexintegrityandmitochondrialdamagebutnottdp43mitochondriallocalisationarelikelyassociatedwithseverityofchchd10relateddiseases AT sandralacasgervais lossofmicoscomplexintegrityandmitochondrialdamagebutnottdp43mitochondriallocalisationarelikelyassociatedwithseverityofchchd10relateddiseases AT manujokela lossofmicoscomplexintegrityandmitochondrialdamagebutnottdp43mitochondriallocalisationarelikelyassociatedwithseverityofchchd10relateddiseases AT mariauranen lossofmicoscomplexintegrityandmitochondrialdamagebutnottdp43mitochondriallocalisationarelikelyassociatedwithseverityofchchd10relateddiseases AT emilylikallio lossofmicoscomplexintegrityandmitochondrialdamagebutnottdp43mitochondriallocalisationarelikelyassociatedwithseverityofchchd10relateddiseases AT alessandramauricrouzet lossofmicoscomplexintegrityandmitochondrialdamagebutnottdp43mitochondriallocalisationarelikelyassociatedwithseverityofchchd10relateddiseases AT hennatyynismaa lossofmicoscomplexintegrityandmitochondrialdamagebutnottdp43mitochondriallocalisationarelikelyassociatedwithseverityofchchd10relateddiseases AT annavihola lossofmicoscomplexintegrityandmitochondrialdamagebutnottdp43mitochondriallocalisationarelikelyassociatedwithseverityofchchd10relateddiseases AT gaelleauge lossofmicoscomplexintegrityandmitochondrialdamagebutnottdp43mitochondriallocalisationarelikelyassociatedwithseverityofchchd10relateddiseases AT charlottecochaud lossofmicoscomplexintegrityandmitochondrialdamagebutnottdp43mitochondriallocalisationarelikelyassociatedwithseverityofchchd10relateddiseases AT hiromisesaki lossofmicoscomplexintegrityandmitochondrialdamagebutnottdp43mitochondriallocalisationarelikelyassociatedwithseverityofchchd10relateddiseases AT jeanehrlandricci lossofmicoscomplexintegrityandmitochondrialdamagebutnottdp43mitochondriallocalisationarelikelyassociatedwithseverityofchchd10relateddiseases AT bjarneudd lossofmicoscomplexintegrityandmitochondrialdamagebutnottdp43mitochondriallocalisationarelikelyassociatedwithseverityofchchd10relateddiseases AT cristofolvivesbauza lossofmicoscomplexintegrityandmitochondrialdamagebutnottdp43mitochondriallocalisationarelikelyassociatedwithseverityofchchd10relateddiseases AT veroniquepaquisflucklinger lossofmicoscomplexintegrityandmitochondrialdamagebutnottdp43mitochondriallocalisationarelikelyassociatedwithseverityofchchd10relateddiseases |
_version_ |
1724207892414857216 |
spelling |
doaj-4dd012f21baf4cd2b4f522f52e36c6f32021-03-22T12:47:03ZengElsevierNeurobiology of Disease1095-953X2018-11-01119159171Loss of MICOS complex integrity and mitochondrial damage, but not TDP-43 mitochondrial localisation, are likely associated with severity of CHCHD10-related diseasesEmmanuelle C. Genin0Sylvie Bannwarth1Françoise Lespinasse2Bernardo Ortega-Vila3Konstantina Fragaki4Kie Itoh5Elodie Villa6Sandra Lacas-Gervais7Manu Jokela8Mari Auranen9Emil Ylikallio10Alessandra Mauri-Crouzet11Henna Tyynismaa12Anna Vihola13Gaelle Augé14Charlotte Cochaud15Hiromi Sesaki16Jean-Ehrland Ricci17Bjarne Udd18Cristofol Vives-Bauza19Véronique Paquis-Flucklinger20Université Côte d'Azur, Inserm, CNRS, IRCAN, CHU de Nice, FranceUniversité Côte d'Azur, Inserm, CNRS, IRCAN, CHU de Nice, FranceUniversité Côte d'Azur, Inserm, CNRS, IRCAN, CHU de Nice, FranceResearch Health Institute of Balearic Islands (IdISB)-Research Unit, Son Espases, University Hospital, SpainUniversité Côte d'Azur, Inserm, CNRS, IRCAN, CHU de Nice, FranceDepartment of Cell Biology, Johns Hopkins University Scholl of Medicine, Baltimore, MD, USAUniversité Côte d'Azur, Inserm, C3M, FranceUniversité Côte d'Azur, Centre Commun de Microscopie Appliquée, FranceNeuromuscular Research Center, Tampere University and University Hospital, Tampere, Finland; Department of Clinical Neurosciences, Turku University Hospital, University of Turku, Turku, FinlandClinical Neurosciences, Neurology, University of Helsinki, Helsinki University Hospital, Helsinki, Finland; Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, FinlandClinical Neurosciences, Neurology, University of Helsinki, Helsinki University Hospital, Helsinki, Finland; Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, FinlandUniversité Côte d'Azur, Inserm, CNRS, IRCAN, CHU de Nice, FranceResearch Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, FinlandFolkhälsan Institute of Genetics, Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, FinlandUniversité Côte d'Azur, Inserm, CNRS, IRCAN, CHU de Nice, FranceUniversité Côte d'Azur, Inserm, CNRS, IRCAN, CHU de Nice, FranceDepartment of Cell Biology, Johns Hopkins University Scholl of Medicine, Baltimore, MD, USAUniversité Côte d'Azur, Inserm, C3M, FranceNeuromuscular Research Center, Tampere University and University Hospital, Tampere, Finland; Folkhälsan Institute of Genetics, Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, FinlandResearch Health Institute of Balearic Islands (IdISB)-Research Unit, Son Espases, University Hospital, SpainUniversité Côte d'Azur, Inserm, CNRS, IRCAN, CHU de Nice, France; Corresponding author at: IRCAN UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, 28 av de Valombrose, 06107 Nice cedex 2, France.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 CHCHD10S59L mutant allele leads to disassembly of mitochondrial contact site and cristae organizing system (MICOS) with mitochondrial 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 CHCHD10G66V 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 CHCHD10S59L 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.http://www.sciencedirect.com/science/article/pii/S0969996118303486CHCHD10SMAJFTD-ALSMitochondriaTDP-43 |