![]() ![]() ![]() CII is anchored between CI and CIV, highlighting the unique architecture and composition of the native supercomplex (Fig. This arrangement is markedly different compared with known mammalian supercomplexes 17, 18 and correlates with the acquisition of four ciliate-specific CI subunits that would clash with the position of CIV as seen in mammals (Fig. CIV 2 is associated with the long side of the membrane region of CI, opposite CIII 2. 1 and 2a–f and Supplementary Tables 1 and 2). Masked refinements resolved individual structures that together form an assembly of 150 different protein subunits and 311 bound lipids (Extended Data Figs. When viewed along the membrane plane, the assembly of more than 300 transmembrane helices displays a bent shape, indicating that the accommodating membrane adopts a local curvature with a radius of approximately 20 nm (Fig. At an overall resolution of 2.9 Å, the structure revealed that CI, CII, CIII 2 and a CIV dimer (CIV 2) associated into a 5.8-MDa supercomplex (Fig. We purified the intact respiratory supercomplex from mitochondria of the ciliate protist Tetrahymena thermophila and determined its structure by single-particle cryo-electron microscopy (cryo-EM) (Extended Data Fig. In ciliates, the inner mitochondrial membrane is organized as tubular cristae, which was previously explained by the helical row assembly of ATP synthase 12, 15, 16. An established mechanism for maintenance of such a topology relies on oligomerization of ATP synthase and its specific interplay with lipids 10, 11, 12, 13, 14. In addition, for the bioenergetic process to occur, a specific topology of the crista membranes that form functionally distinct high-potential compartments is critical 9. ![]() Although CII has been suggested to interact with mammalian ETC complexes 4, 5, 6, 7, 8, it was not experimentally found as part of any characterized supercomplex. CII transfers electrons from succinate via its covalently bound flavin adenine dinucleotide (FAD) and iron–sulfur clusters to UQ and is also a component of the tricarboxylic acid cycle, making a functional link between the two central metabolic pathways 3. Biochemical and structural analyses have shown that these components can organize into supercomplexes containing CI, CIII dimer (CIII 2) and CIV 1, 2. The ETC consists of four multisubunit membrane complexes: complex I (CI NADH:ubiquinone (UQ) oxidoreductase), complex II (CII succinate:UQ oxidoreductase), complex III (CIII cytochrome bc 1) and complex IV (CIV cytochrome c oxidase). Mitochondrial energy conversion requires an electron transport chain (ETC) that generates a proton motive force across the inner mitochondrial membrane to drive the essential adenosine triphosphate (ATP) formation by F 1F o-ATP synthase. Our findings highlight how the evolution of protein subunits of respiratory complexes has led to the I–II–III 2–IV 2 supercomplex that contributes to the shaping of the bioenergetic membrane, thereby enabling its functional specialization. Using molecular dynamics simulations, we demonstrate that the divergent supercomplex actively contributes to the membrane curvature induction and tubulation of cristae. Together with a tilted complex III dimer association, it results in a curved membrane region. Owing to subunit acquisition and extension, complex I associates with a complex IV dimer, generating a wedge-shaped gap that serves as a binding site for complex II. We report cryo-electron microscopy and cryo-tomography structures of the supercomplex that comprises 150 different proteins and 311 bound lipids, forming a stable 5.8-MDa assembly. Here we show that a supercomplex containing all four respiratory chain components contributes to membrane curvature induction in ciliates. Mitochondrial energy conversion requires an intricate architecture of the inner mitochondrial membrane 1. ![]()
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