We show that the mitochondrial fission proteins MiD49 and MiD51 are activated by fatty acyl-coenzyme A (FA-CoA). FA-CoA binds in a previously identified pocket located within MiDs, inducing their oligomerization and ability to activate the dynamin DRP1, ultimately promoting mitochondrial fission. Activated MiDs synergize with mitochondrial fission factor (MFF) in stimulating DRP1 activity, leading us to hypothesize that MiDs act upstream of MFF during mitochondrial fission.
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References
Losón, O. C. et al. The mitochondrial fission receptor MiD51 requires ADP as a cofactor. Structure 22, 367–377 (2014). This paper reports that MiD51 binds ADP or GDP, and that mutants in this binding site inhibit mitochondrial fission.
Richter, V. et al. Structural and functional analysis of MiD51, a dynamin receptor required for mitochondrial fission. J. Cell Biol. 204, 477–488 (2014). This paper reports that MiD51 binds ADP or GDP in slightly different orientations.
Losón, O. C. et al. Crystal structure and functional analysis of MiD49, a receptor for the mitochondrial fission protein Drp1. Protein Sci. 24, 386–394 (2015). This paper reports that MiD49 has a putative binding pocket, but that the ligand for this pocket is unknown.
Palmer, C. S. et al. MiD49 and MiD51, new components of the mitochondrial fission machinery. EMBO Rep. 12, 565–573 (2011). This paper shows the surprising result that both knockdown and overexpression of MiD49 or MiD51 cause mitochondrial elongation, with knockdown reducing and overexpression increasing mitochondrial DRP1 recruitment.
Ngo, J. et al. Mitochondrial morphology controls fatty acid utilization by changing CPT1 sensitivity to malonyl-CoA. EMBO J. 42, e111901 (2023). This paper shows that increased fatty acid oxidation correlates with increased mitochondrial fission in several cellular contexts.
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This is a summary of: Liu, A. et al. Fatty acyl-coenzyme A activates mitochondrial division through oligomerization of MiD49 and MiD51. Nat. Cell Biol. https://doi.org/10.1038/s41556-024-01400-3 (2024).
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Regulation of mitochondrial fission by fatty acyl-coenzyme A. Nat Cell Biol (2024). https://doi.org/10.1038/s41556-024-01406-x
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DOI: https://doi.org/10.1038/s41556-024-01406-x
