Structural basis of mitochondrial membrane bending by the I–II–III2–IV2 supercomplex

Abstract

Mitochondrial energy conversion requires an intricate architecture of the inner mitochondrial membrane1. Here we show that a supercomplex containing all four respiratory chain components contributes to membrane curvature induction in ciliates. 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. 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. Together with a tilted complex III dimer association, it results in a curved membrane region. Using molecular dynamics simulations, we demonstrate that the divergent supercomplex actively contributes to the membrane curvature induction and tubulation of cristae. Our findings highlight how the evolution of protein subunits of respiratory complexes has led to the I–II–III2–IV2 supercomplex that contributes to the shaping of the bioenergetic membrane, thereby enabling its functional specialization.

Chelation of the Optimal Antifungal Pogostone Analogue with Copper(II) to Explore the Dual Antifungal and Antibacterial Agent

“…Besides, X-ray crystallography reportedly revealed that atpenin A5 binds essentially where UQ does in native CII . CIII also contains UQ-binding sites to accommodate the electron transporter ubiquinol from CII. , These facts prompted us to further explore whether 21 would hold the inhibition activity against CIII. The results of enzyme activity assays showed that 21 exerted moderate CIII inhibition activity with an IC 50 value of 0.79 μg/mL (Figure S13), while boscalid lacked apparent activity up to 1.0 μg/mL.…”

Pragmatic Coarse-Graining of Proteins: Models and Applications

“…An entire 120 MDa human nuclear pore complex, responsible for facilitating nucleocytoplasmic transport, was also recently modeled and simulated for over 1 μs (Figure , e). A 5.8 MDa mitochondrial respiratory complex has also been simulated using Martini, showcasing how it impacts the curvature of the surrounding membrane region (Figure , d). Additionally, Martini has been applied to model the SARS-CoV and SARS-CoV-2 − envelope structures.…”

“…(d) Snapshot showing the arched membrane region generated by the mitochondrial respiratory supercomplex. Reproduced with permission from ref . Copyright 2023 Springer Nature.…”

Using cryo-EM to understand the assembly pathway of respiratory complex I

“…Initial cryo-EM work was focused on Y. lipolytica (Parey et al, 2018(Parey et al, , 2019 and mammalian species including Bos taurus (Zhu et al, 2016;Blaza et al, 2018), Ovis aries (Fiedorczuk et al, 2016;Letts et al, 2019), Sus scrofa (Wu et al, 2016), Mus musculus (Agip et al, 2018;Bridges et al, 2020) and Homo sapiens (Guo et al, 2017). More recently, structures have been determined from several other species, including Escherichia coli (Kolata & Efremov, 2021;Kravchuk et al, 2022), plants (Maldonado et al, 2020(Maldonado et al, , 2023Soufari et al, 2020;Klusch et al, 2021Klusch et al, , 2023, thermophilic fungi (Laube et al, 2022), insects (Agip et al, 2023;Padavannil et al, 2023) and ciliates (Zhou et al, 2022;Mu ¨hleip et al, 2023).…”