8UCA

Formation of I2+III2 supercomplex rescues respiratory chain defects

This is a non-PDB format compatible entry.

Summary for 8UCA

• Entry DOI: 10.2210/pdb8uca/pdb
• EMDB information: 42122 42123
• Descriptor: 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)
• Functional Keywords: super complex xl (ci2+ciii2), electron transport, translocase
• Biological source: Mus musculus (house mouse); More
• Total number of polymer chains: 111
• Total formula weight: 2577848.16

Authors

Letts, J.A.,Padavannil, A. (deposition date: 2023-09-26, release date: 2025-01-15, Last modification date: 2025-02-19)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (3.7 Å)