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Structural insights into cardiolipin replacement by phosphatidylglycerol in a cardiolipin-lacking yeast respiratory supercomplex

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 supe...

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Published in:Nature communications 2023-05, Vol.14 (1), p.2783-2783, Article 2783
Main Authors: Hryc, Corey F., Mallampalli, Venkata K. P. S., Bovshik, Evgeniy I., Azinas, Stavros, Fan, Guizhen, Serysheva, Irina I., Sparagna, Genevieve C., Baker, Matthew L., Mileykovskaya, Eugenia, Dowhan, William
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Language:English
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Summary: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 (IV 1 III 2 IV 1 ) and a supercomplex (III 2 IV 1 ) isolated from a cardiolipin-lacking Saccharomyces cerevisiae mutant at 3.2-Å and 3.3-Å resolution, respectively, and demonstrate that phosphatidylglycerol in III 2 IV 1 occupies similar positions as cardiolipin in IV 1 III 2 IV 1 . Lipid-protein interactions within these complexes differ, which conceivably underlies the reduced level of IV 1 III 2 IV 1 and high levels of III 2 IV 1 and free III 2 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. Whether anionic phospholipids required for respiratory supercomplex (SC) formation is unclear. Here authors resolve SCs from a wild type and cardiolipin-deficient yeast strain at 3.2- 3.3 Å resolution to show that cardiolipin can be replaced by phosphatidylglycerol.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-023-38441-5