2. Academic Validation
  3. SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome

SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome

  • EMBO Mol Med. 2016 Sep 1;8(9):1019-38. doi: 10.15252/emmm.201506159.
Alexandre Janer 1,  Julien Prudent 2,  Vincent Paupe 1,  Somayyeh Fahiminiya 3,  Jacek Majewski 3,  Nicolas Sgarioto 4,  Christine Des Rosiers 5,  Anik Forest 5,  Zhen-Yuan Lin 6,  Anne-Claude Gingras 7,  Grant Mitchell 8,  Heidi M McBride 2,  Eric A Shoubridge 9
Affiliations

Affiliations

  • 1 Department of Human Genetics, McGill University, Montreal, QC, Canada Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
  • 2 Montreal Neurological Institute, McGill University, Montreal, QC, Canada Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
  • 3 Department of Human Genetics, McGill University, Montreal, QC, Canada.
  • 4 Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
  • 5 Department of Nutrition, Université de Montréal, Montreal, QC, Canada Research Centre, Montreal Heart Institute, Montreal, QC, Canada.
  • 6 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
  • 7 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
  • 8 Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Montreal, QC, Canada.
  • 9 Department of Human Genetics, McGill University, Montreal, QC, Canada Montreal Neurological Institute, McGill University, Montreal, QC, Canada eric@ericpc.mni.mcgill.ca.
PMID: 27390132 DOI: 10.15252/emmm.201506159
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.

Keywords

Leigh syndrome; SLC25A46; mitochondrial architecture; phospholipid transfer.

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