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

Alexandre Janer,Anne‐Claude Gingras,Grant Mitchell,Heidi M Mcbride,Anik Forest,Julien Prudent,Nicolas Sgarioto,Vincent Paupe,Zhen‐Yuan Lin,Jacek Majewski,Eric A Shoubridge,Somayyeh Fahiminiya,Christine Des Rosiers

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.

Highlights

Mitochondria form a dynamic network that responds to physiological signals and metabolic stresses by altering the balance between fusion and fission
The subject presented with Leigh syndrome, an early-onset and fatal neurodegenerative disease associated with bilaterally symmetric lesions in the brainstem, basal ganglia, and spinal cord (Leigh, 1951)
Phylogenetic analysis of the mitochondrial metabolite carrier proteins in human, yeast, and plants showed that SLC25A46 is most closely related to Ugo1, an outer membrane protein in yeast that is essential for mitochondrial membrane fusion (Sesaki & Jensen, 2001; Coonrod et al, 2007; Hoppins et al, 2009; Anton et al, 2011; Papic et al, 2011), suggesting that they are orthologous (Haferkamp & Schmitz-Esser, 2012)

Summary

Introduction

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 Ugo, a mitochondrial metabolite carrier family protein. 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. SLC25A46 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

Methods

Results

Conclusion