Cardiolipin is a hallmark phospholipid of mitochondrial membranes. Despite established significance of cardiolipin in supporting respiratory supercomplex organization, a mechanistic understanding of this lipid-protein interaction is still lacking. To address the essential role of cardiolipin in supercomplex organization, we report cryo-EM structures of a wild type supercomplex (IV₁III₂IV₁) and a supercomplex (III₂IV₁) isolated from a cardiolipin-lacking Saccharomyces cerevisiae mutant at 3.2-Å and 3.3-Å resolution, respectively, and demonstrate that phosphatidylglycerol in III₂IV₁ occupies similar positions as cardiolipin in IV₁III₂IV₁. Lipid-protein interactions within these complexes differ, which conceivably underlies the reduced level of IV₁III₂IV₁ and high levels of III₂IV₁ and free III₂ and IV in mutant mitochondria. Here we show that anionic phospholipids interact with positive amino acids and appear to nucleate a phospholipid domain at the interface between the individual complexes, which dampen charge repulsion and further stabilize interaction, respectively, between individual complexes.

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Journal Article | Research Support, N.I.H., Extramural | Research Support, Non-U.S. Gov't

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Hryc CF, Mallampalli VKPS, Bovshik EI, Azinas S, Fan G, Serysheva II, Sparagna GC, Baker ML, Mileykovskaya E, Dowhan W

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