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bioRxiv · 10.1101/2023.12.29.573615

Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Mfn2 and Opa1

Boopathy, S.·Lugo, C. M.·Luce, B. E.·McDonald, J. L.·Hakim, P.·Ponce, J.·Ueberheide, B.·Chao, L. H.
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Abstract

Mitochondrial fusion requires the sequential merger of four bilayers to two. The outer-membrane solute carrier protein SLC25A46 interacts with both the outer and inner-membrane dynamin family GTPases Mfn1/2 and Opa1. While SLC25A46 levels are known to affect mitochondrial morphology, how SLC25A46 interacts with Mfn1/2 and Opa1 to regulate membrane fusion is not understood. In this study, we use crosslinking mass-spectrometry and AlphaFold 2 modeling to identify interfaces mediating a SLC25A46 interactions with Opa1 and Mfn2. We reveal that the bundle signaling element of Opa1 interacts with SLC25A46, and present evidence of a Mfn2 interaction involving the SLC25A46 cytosolic face. We validate these newly identified interaction interfaces and show that they play a role in mitochondrial network maintenance.

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Boopathy, S., Lugo, C. M., Luce, B. E., McDonald, J. L., Hakim, P., Ponce, J., Ueberheide, B., Chao, L. H.. 2023-12-29. Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Mfn2 and Opa1. https://doi.org/10.1101/2023.12.29.573615

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