CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis
Abstract CHCHD10‐related diseases include mitochondrial DNA instability disorder, frontotemporal dementia‐amyotrophic lateral sclerosis (FTD‐ALS) clinical spectrum, late‐onset spinal motor neuropathy (SMAJ), and Charcot–Marie–Tooth disease type 2 (CMT2). Here, we show that CHCHD10 resides with mitof...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2015-12-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201505496 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849332227524001792 |
|---|---|
| author | Emmanuelle C Genin Morgane Plutino Sylvie Bannwarth Elodie Villa Eugenia Cisneros‐Barroso Madhuparna Roy Bernardo Ortega‐Vila Konstantina Fragaki Françoise Lespinasse Estefania Pinero‐Martos Gaëlle Augé David Moore Florence Burté Sandra Lacas‐Gervais Yusuke Kageyama Kie Itoh Patrick Yu‐Wai‐Man Hiromi Sesaki Jean‐Ehrland Ricci Cristofol Vives‐Bauza Véronique Paquis‐Flucklinger |
| author_facet | Emmanuelle C Genin Morgane Plutino Sylvie Bannwarth Elodie Villa Eugenia Cisneros‐Barroso Madhuparna Roy Bernardo Ortega‐Vila Konstantina Fragaki Françoise Lespinasse Estefania Pinero‐Martos Gaëlle Augé David Moore Florence Burté Sandra Lacas‐Gervais Yusuke Kageyama Kie Itoh Patrick Yu‐Wai‐Man Hiromi Sesaki Jean‐Ehrland Ricci Cristofol Vives‐Bauza Véronique Paquis‐Flucklinger |
| author_sort | Emmanuelle C Genin |
| collection | DOAJ |
| description | Abstract CHCHD10‐related diseases include mitochondrial DNA instability disorder, frontotemporal dementia‐amyotrophic lateral sclerosis (FTD‐ALS) clinical spectrum, late‐onset spinal motor neuropathy (SMAJ), and Charcot–Marie–Tooth disease type 2 (CMT2). Here, we show that CHCHD10 resides with mitofilin, CHCHD3 and CHCHD6 within the “mitochondrial contact site and cristae organizing system” (MICOS) complex. CHCHD10 mutations lead to MICOS complex disassembly and loss of mitochondrial cristae with a decrease in nucleoid number and nucleoid disorganization. Repair of the mitochondrial genome after oxidative stress is impaired in CHCHD10 mutant fibroblasts and this likely explains the accumulation of deleted mtDNA molecules in patient muscle. CHCHD10 mutant fibroblasts are not defective in the delivery of mitochondria to lysosomes suggesting that impaired mitophagy does not contribute to mtDNA instability. Interestingly, the expression of CHCHD10 mutant alleles inhibits apoptosis by preventing cytochrome c release. |
| format | Article |
| id | doaj-art-a6eda45384124c2da28b788438fcf63d |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2015-12-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-a6eda45384124c2da28b788438fcf63d2025-08-20T03:46:16ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842015-12-0181587210.15252/emmm.201505496CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosisEmmanuelle C Genin0Morgane Plutino1Sylvie Bannwarth2Elodie Villa3Eugenia Cisneros‐Barroso4Madhuparna Roy5Bernardo Ortega‐Vila6Konstantina Fragaki7Françoise Lespinasse8Estefania Pinero‐Martos9Gaëlle Augé10David Moore11Florence Burté12Sandra Lacas‐Gervais13Yusuke Kageyama14Kie Itoh15Patrick Yu‐Wai‐Man16Hiromi Sesaki17Jean‐Ehrland Ricci18Cristofol Vives‐Bauza19Véronique Paquis‐Flucklinger20IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia‐Antipolis UniversityIRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia‐Antipolis UniversityIRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia‐Antipolis UniversityINSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), équipe “contrôle métabolique des morts cellulaires”, Nice Sophia‐Antipolis UniversityResearch Health Institute of Palma (IdISPa), Research Unit, Son Espases University HospitalDepartment of Cell Biology, Johns Hopkins University School of MedicineResearch Health Institute of Palma (IdISPa), Research Unit, Son Espases University HospitalIRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia‐Antipolis UniversityIRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia‐Antipolis UniversityResearch Health Institute of Palma (IdISPa), Research Unit, Son Espases University HospitalIRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia‐Antipolis UniversityWellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, International Centre for Life, Newcastle UniversityWellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, International Centre for Life, Newcastle UniversityJoint Center for Applied Electron Microscopy, Nice Sophia‐Antipolis UniversityDepartment of Cell Biology, Johns Hopkins University School of MedicineDepartment of Cell Biology, Johns Hopkins University School of MedicineWellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, International Centre for Life, Newcastle UniversityDepartment of Cell Biology, Johns Hopkins University School of MedicineINSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), équipe “contrôle métabolique des morts cellulaires”, Nice Sophia‐Antipolis UniversityResearch Health Institute of Palma (IdISPa), Research Unit, Son Espases University HospitalIRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia‐Antipolis UniversityAbstract CHCHD10‐related diseases include mitochondrial DNA instability disorder, frontotemporal dementia‐amyotrophic lateral sclerosis (FTD‐ALS) clinical spectrum, late‐onset spinal motor neuropathy (SMAJ), and Charcot–Marie–Tooth disease type 2 (CMT2). Here, we show that CHCHD10 resides with mitofilin, CHCHD3 and CHCHD6 within the “mitochondrial contact site and cristae organizing system” (MICOS) complex. CHCHD10 mutations lead to MICOS complex disassembly and loss of mitochondrial cristae with a decrease in nucleoid number and nucleoid disorganization. Repair of the mitochondrial genome after oxidative stress is impaired in CHCHD10 mutant fibroblasts and this likely explains the accumulation of deleted mtDNA molecules in patient muscle. CHCHD10 mutant fibroblasts are not defective in the delivery of mitochondria to lysosomes suggesting that impaired mitophagy does not contribute to mtDNA instability. Interestingly, the expression of CHCHD10 mutant alleles inhibits apoptosis by preventing cytochrome c release.https://doi.org/10.15252/emmm.201505496CHCHD10mitochondriamitochondrial diseasemotor neuron diseasemtDNA instability |
| spellingShingle | Emmanuelle C Genin Morgane Plutino Sylvie Bannwarth Elodie Villa Eugenia Cisneros‐Barroso Madhuparna Roy Bernardo Ortega‐Vila Konstantina Fragaki Françoise Lespinasse Estefania Pinero‐Martos Gaëlle Augé David Moore Florence Burté Sandra Lacas‐Gervais Yusuke Kageyama Kie Itoh Patrick Yu‐Wai‐Man Hiromi Sesaki Jean‐Ehrland Ricci Cristofol Vives‐Bauza Véronique Paquis‐Flucklinger CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis EMBO Molecular Medicine CHCHD10 mitochondria mitochondrial disease motor neuron disease mtDNA instability |
| title | CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis |
| title_full | CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis |
| title_fullStr | CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis |
| title_full_unstemmed | CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis |
| title_short | CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis |
| title_sort | chchd10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis |
| topic | CHCHD10 mitochondria mitochondrial disease motor neuron disease mtDNA instability |
| url | https://doi.org/10.15252/emmm.201505496 |
| work_keys_str_mv | AT emmanuellecgenin chchd10mutationspromotelossofmitochondrialcristaejunctionswithimpairedmitochondrialgenomemaintenanceandinhibitionofapoptosis AT morganeplutino chchd10mutationspromotelossofmitochondrialcristaejunctionswithimpairedmitochondrialgenomemaintenanceandinhibitionofapoptosis AT sylviebannwarth chchd10mutationspromotelossofmitochondrialcristaejunctionswithimpairedmitochondrialgenomemaintenanceandinhibitionofapoptosis AT elodievilla chchd10mutationspromotelossofmitochondrialcristaejunctionswithimpairedmitochondrialgenomemaintenanceandinhibitionofapoptosis AT eugeniacisnerosbarroso chchd10mutationspromotelossofmitochondrialcristaejunctionswithimpairedmitochondrialgenomemaintenanceandinhibitionofapoptosis AT madhuparnaroy chchd10mutationspromotelossofmitochondrialcristaejunctionswithimpairedmitochondrialgenomemaintenanceandinhibitionofapoptosis AT bernardoortegavila chchd10mutationspromotelossofmitochondrialcristaejunctionswithimpairedmitochondrialgenomemaintenanceandinhibitionofapoptosis AT konstantinafragaki chchd10mutationspromotelossofmitochondrialcristaejunctionswithimpairedmitochondrialgenomemaintenanceandinhibitionofapoptosis AT francoiselespinasse chchd10mutationspromotelossofmitochondrialcristaejunctionswithimpairedmitochondrialgenomemaintenanceandinhibitionofapoptosis AT estefaniapineromartos chchd10mutationspromotelossofmitochondrialcristaejunctionswithimpairedmitochondrialgenomemaintenanceandinhibitionofapoptosis AT gaelleauge chchd10mutationspromotelossofmitochondrialcristaejunctionswithimpairedmitochondrialgenomemaintenanceandinhibitionofapoptosis AT davidmoore chchd10mutationspromotelossofmitochondrialcristaejunctionswithimpairedmitochondrialgenomemaintenanceandinhibitionofapoptosis AT florenceburte chchd10mutationspromotelossofmitochondrialcristaejunctionswithimpairedmitochondrialgenomemaintenanceandinhibitionofapoptosis AT sandralacasgervais chchd10mutationspromotelossofmitochondrialcristaejunctionswithimpairedmitochondrialgenomemaintenanceandinhibitionofapoptosis AT yusukekageyama chchd10mutationspromotelossofmitochondrialcristaejunctionswithimpairedmitochondrialgenomemaintenanceandinhibitionofapoptosis AT kieitoh chchd10mutationspromotelossofmitochondrialcristaejunctionswithimpairedmitochondrialgenomemaintenanceandinhibitionofapoptosis AT patrickyuwaiman chchd10mutationspromotelossofmitochondrialcristaejunctionswithimpairedmitochondrialgenomemaintenanceandinhibitionofapoptosis AT hiromisesaki chchd10mutationspromotelossofmitochondrialcristaejunctionswithimpairedmitochondrialgenomemaintenanceandinhibitionofapoptosis AT jeanehrlandricci chchd10mutationspromotelossofmitochondrialcristaejunctionswithimpairedmitochondrialgenomemaintenanceandinhibitionofapoptosis AT cristofolvivesbauza chchd10mutationspromotelossofmitochondrialcristaejunctionswithimpairedmitochondrialgenomemaintenanceandinhibitionofapoptosis AT veroniquepaquisflucklinger chchd10mutationspromotelossofmitochondrialcristaejunctionswithimpairedmitochondrialgenomemaintenanceandinhibitionofapoptosis |