abberior instruments
2023
Life Science Alliance
The role of the mitochondrial outer membrane protein SLC25A46 in mitochondrial fission and fusion
Authors:
Jana Schuettpelz, Alexandre Janer, Hana Antonicka, Eric A Shoubridge
Keywords:
Mitochondria, Membranes
Abstract:
Mutations in SLC25A46 underlie a wide spectrum of neurodegenerative diseases associated with alterations in mitochondrial morphology. We established an SLC25A46 knock-out cell line in human fibroblasts and studied the pathogenicity of three variants (p.T142I, p.R257Q, and p.E335D). Mitochondria were fragmented in the knock-out cell line and hyperfused in all pathogenic variants. The loss of SLC25A46 led to abnormalities in the mitochondrial cristae ultrastructure that were not rescued by the expression of the variants. SLC25A46 was present in discrete puncta at mitochondrial branch points and tips of mitochondrial tubules, co-localizing with DRP1 and OPA1. Virtually, all fission/fusion events were demarcated by a SLC25A46 focus. SLC25A46 co-immunoprecipitated with the fusion machinery, and loss of function altered the oligomerization state of OPA1 and MFN2. Proximity interaction mapping identified components of the ER membrane, lipid transfer proteins, and mitochondrial outer membrane proteins, indicating that it is present at interorganellar contact sites. SLC25A46 loss of function led to altered mitochondrial lipid composition, suggesting that it may facilitate interorganellar lipid flux or play a role in membrane remodeling associated with mitochondrial fusion and fission.