Structure of the II2-III2-IV2 mitochondrial supercomplex from the para-site Perkinsus marinus

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Structure of the II2-III2-IV2 mitochondrial supercomplex from the para-site Perkinsus marinus


Wu, F.; Muhleip, A.; Gruhl, T.; Sheiner, L.; Marechal, A.; Amunts, A.


Respiratory complexes have co-evolved into supercomplexes in different clades to sustain energy production at the basis of eukaryotic life. In parasites, they likely exhibit functional and compositional distinctions. In this study, using cryogenic electron microscopy, we determined the 2.1 Angstrom resolution structure of a 104-subunit II2-III2-IV2 supercomplex from the parasite Perkinsus marinus, related to Apicomplexa, capable of complete electron transport from succinate to molecular oxygen. A feature of the para-site is the association of two copies of complex II via the apicomplexan subunit SDHG that interacts with both complexes III and IV and bridge the supercomplex. In the c1 state, we identified two protein factors, ISPR1 and ISPR2 bound on the surface of complex III, where cytochrome c docks, acting as potential regulators. The acquisition of 15 specific subunits to complex IV results in its lateral offset, increasing the distance between the cyt c electron donor and acceptor sites. This is compensated by conformational dynamics in the membrane, supported by peripheral interactions of both complex IV monomers with each complex III copy. The domain homologous to canonical mitochondria-encoded transmembrane subunit COX2 is made of three separate polypeptides encoded in the nucleus, and their correct assembly is a prerequisite for electron transport in the supercomplex. Cyt b and COX1 comprise a +2 frameshift introduced during protein synthesis by the mitoribosome. Among 114 modelled endogenous lipids, we detect a direct contribution to the formation of the divergent supercomplex and its functional sites, including assembly of CII and ubiquinone binding. Our findings ex-pose the uniqueness of the principal components of bioenergetics in the mitochondria of parasites.

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