SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome
Abstract Mitochondria form a dynamic network that responds to physiological signals and metabolic stresses by altering the balance between fusion and fission. Mitochondrial fusion is orchestrated by conserved GTPases MFN1/2 and OPA1, a process coordinated in yeast by Ugo1, a mitochondrial metabolite...
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| Format: | Article |
| Language: | English |
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Springer Nature
2016-07-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201506159 |
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| author | Alexandre Janer Julien Prudent Vincent Paupe Somayyeh Fahiminiya Jacek Majewski Nicolas Sgarioto Christine Des Rosiers Anik Forest Zhen‐Yuan Lin Anne‐Claude Gingras Grant Mitchell Heidi M McBride Eric A Shoubridge |
| author_facet | Alexandre Janer Julien Prudent Vincent Paupe Somayyeh Fahiminiya Jacek Majewski Nicolas Sgarioto Christine Des Rosiers Anik Forest Zhen‐Yuan Lin Anne‐Claude Gingras Grant Mitchell Heidi M McBride Eric A Shoubridge |
| author_sort | Alexandre Janer |
| collection | DOAJ |
| description | Abstract Mitochondria form a dynamic network that responds to physiological signals and metabolic stresses by altering the balance between fusion and fission. Mitochondrial fusion is orchestrated by conserved GTPases MFN1/2 and OPA1, a process coordinated in yeast by Ugo1, a mitochondrial metabolite carrier family protein. We uncovered a homozygous missense mutation in SLC25A46, the mammalian orthologue of Ugo1, in a subject with Leigh syndrome. SLC25A46 is an integral outer membrane protein that interacts with MFN2, OPA1, and the mitochondrial contact site and cristae organizing system (MICOS) complex. The subject mutation destabilizes the protein, leading to mitochondrial hyperfusion, alterations in endoplasmic reticulum (ER) morphology, impaired cellular respiration, and premature cellular senescence. The MICOS complex is disrupted in subject fibroblasts, resulting in strikingly abnormal mitochondrial architecture, with markedly shortened cristae. SLC25A46 also interacts with the ER membrane protein complex EMC, and phospholipid composition is altered in subject mitochondria. These results show that SLC25A46 plays a role in a mitochondrial/ER pathway that facilitates lipid transfer, and link altered mitochondrial dynamics to early‐onset neurodegenerative disease and cell fate decisions. |
| format | Article |
| id | doaj-art-22810f2315b34bb8997e0edcfcab588d |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2016-07-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-22810f2315b34bb8997e0edcfcab588d2025-08-20T03:06:00ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842016-07-01891019103810.15252/emmm.201506159SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndromeAlexandre Janer0Julien Prudent1Vincent Paupe2Somayyeh Fahiminiya3Jacek Majewski4Nicolas Sgarioto5Christine Des Rosiers6Anik Forest7Zhen‐Yuan Lin8Anne‐Claude Gingras9Grant Mitchell10Heidi M McBride11Eric A Shoubridge12Department of Human Genetics, McGill UniversityMontreal Neurological Institute, McGill UniversityDepartment of Human Genetics, McGill UniversityDepartment of Human Genetics, McGill UniversityDepartment of Human Genetics, McGill UniversityMontreal Neurological Institute, McGill UniversityDepartment of Nutrition, Université de MontréalDepartment of Nutrition, Université de MontréalLunenfeld‐Tanenbaum Research Institute, Mount Sinai HospitalLunenfeld‐Tanenbaum Research Institute, Mount Sinai HospitalDivision of Medical Genetics, Department of Pediatrics, CHU Sainte‐Justine and Université de MontréalMontreal Neurological Institute, McGill UniversityDepartment of Human Genetics, McGill UniversityAbstract Mitochondria form a dynamic network that responds to physiological signals and metabolic stresses by altering the balance between fusion and fission. Mitochondrial fusion is orchestrated by conserved GTPases MFN1/2 and OPA1, a process coordinated in yeast by Ugo1, a mitochondrial metabolite carrier family protein. We uncovered a homozygous missense mutation in SLC25A46, the mammalian orthologue of Ugo1, in a subject with Leigh syndrome. SLC25A46 is an integral outer membrane protein that interacts with MFN2, OPA1, and the mitochondrial contact site and cristae organizing system (MICOS) complex. The subject mutation destabilizes the protein, leading to mitochondrial hyperfusion, alterations in endoplasmic reticulum (ER) morphology, impaired cellular respiration, and premature cellular senescence. The MICOS complex is disrupted in subject fibroblasts, resulting in strikingly abnormal mitochondrial architecture, with markedly shortened cristae. SLC25A46 also interacts with the ER membrane protein complex EMC, and phospholipid composition is altered in subject mitochondria. These results show that SLC25A46 plays a role in a mitochondrial/ER pathway that facilitates lipid transfer, and link altered mitochondrial dynamics to early‐onset neurodegenerative disease and cell fate decisions.https://doi.org/10.15252/emmm.201506159Leigh syndromemitochondrial architecturephospholipid transferSLC25A46 |
| spellingShingle | Alexandre Janer Julien Prudent Vincent Paupe Somayyeh Fahiminiya Jacek Majewski Nicolas Sgarioto Christine Des Rosiers Anik Forest Zhen‐Yuan Lin Anne‐Claude Gingras Grant Mitchell Heidi M McBride Eric A Shoubridge SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome EMBO Molecular Medicine Leigh syndrome mitochondrial architecture phospholipid transfer SLC25A46 |
| title | SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome |
| title_full | SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome |
| title_fullStr | SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome |
| title_full_unstemmed | SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome |
| title_short | SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome |
| title_sort | slc25a46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for leigh syndrome |
| topic | Leigh syndrome mitochondrial architecture phospholipid transfer SLC25A46 |
| url | https://doi.org/10.15252/emmm.201506159 |
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