title: 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 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.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Janer
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, QC, Canada Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
authors.forename: Julien
authors.initials: J
authors.lastname: Prudent
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
authors.forename: Vincent
authors.initials: V
authors.lastname: Paupe
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada.
authors.forename: Somayyeh
authors.initials: S
authors.lastname: Fahiminiya
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sgarioto
authors.affiliation: Department of Nutrition, Université de Montréal, Montreal, QC, Canada Research Centre, Montreal Heart Institute, Montreal, QC, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Des Rosiers
authors.affiliation: Department of Nutrition, Université de Montréal, Montreal, QC, Canada Research Centre, Montreal Heart Institute, Montreal, QC, Canada.
authors.forename: Anik
authors.initials: A
authors.lastname: Forest
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: Zhen-Yuan
authors.initials: ZY
authors.lastname: Lin
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Gingras
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Montreal, QC, Canada.
authors.forename: Grant
authors.initials: G
authors.lastname: Mitchell
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, QC, Canada Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
authors.forename: Heidi M
authors.initials: HM
authors.lastname: McBride
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada Montreal Neurological Institute, McGill University, Montreal, QC, Canada eric@ericpc.mni.mcgill.ca.
authors.forename: Eric A
authors.identifier: 0000-0003-1498-9473
authors.initials: EA
authors.lastname: Shoubridge
mesh_terms: D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D006706:Homeostasis; D006801:Humans; D007888:Leigh Disease / Q000235:genetics / Q000473:pathology*; D050356:Lipid Metabolism; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D028061:Phosphate Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D024101:Mitochondrial Proteins; D028061:Phosphate Transport Proteins; C584459:SLC25A46 protein, human
keywords: Leigh syndrome; SLC25A46; mitochondrial architecture; phospholipid transfer