8UCA

Formation of I2+III2 supercomplex rescues respiratory chain defects

これはPDB形式変換不可エントリーです。

8UCA の概要

• エントリーDOI: 10.2210/pdb8uca/pdb
• EMDBエントリー: 42122 42123
• 分子名称: NADH-ubiquinone oxidoreductase chain 3, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mitochondrial, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mitochondrial, ... (65 entities in total)
• 機能のキーワード: super complex xl (ci2+ciii2), electron transport, translocase
• 由来する生物種: Mus musculus (house mouse); 詳細
• タンパク質・核酸の鎖数: 111
• 化学式量合計: 2577848.16

構造登録者

Letts, J.A.,Padavannil, A. (登録日: 2023-09-26, 公開日: 2025-01-15, 最終更新日: 2025-02-19)

主引用文献

Liang, C.,Padavannil, A.,Zhang, S.,Beh, S.,Robinson, D.R.L.,Meisterknecht, J.,Cabrera-Orefice, A.,Koves, T.R.,Watanabe, C.,Watanabe, M.,Illescas, M.,Lim, R.,Johnson, J.M.,Ren, S.,Wu, Y.J.,Kappei, D.,Ghelli, A.M.,Funai, K.,Osaka, H.,Muoio, D.,Ugalde, C.,Wittig, I.,Stroud, D.A.,Letts, J.A.,Ho, L.
Formation of I 2 +III 2 supercomplex rescues respiratory chain defects.
Cell Metab., 37:441-459.e11, 2025

PubMed Abstract: Mitochondrial electron transport chain (ETC) complexes partition between free complexes and quaternary assemblies known as supercomplexes (SCs). However, the physiological requirement for SCs and the mechanisms regulating their formation remain controversial. Here, we show that genetic perturbations in mammalian ETC complex III (CIII) biogenesis stimulate the formation of a specialized extra-large SC (SC-XL) with a structure of I+III, resolved at 3.7 Å by cryoelectron microscopy (cryo-EM). SC-XL formation increases mitochondrial cristae density, reduces CIII reactive oxygen species (ROS), and sustains normal respiration despite a 70% reduction in CIII activity, effectively rescuing CIII deficiency. Consequently, inhibiting SC-XL formation in CIII mutants using the Uqcrc1 contact site mutation leads to respiratory decompensation. Lastly, SC-XL formation promotes fatty acid oxidation (FAO) and protects against ischemic heart failure in mice. Our study uncovers an unexpected plasticity in the mammalian ETC, where structural adaptations mitigate intrinsic perturbations, and suggests that manipulating SC-XL formation is a potential therapeutic strategy for mitochondrial dysfunction.

PubMed: 39788125
DOI: 10.1016/j.cmet.2024.11.011

実験手法

ELECTRON MICROSCOPY (3.7 Å)