Cell Metab. 2025 Jan 08. pii: S1550-4131(24)00457-1. [Epub ahead of print]
Chao Liang,
Abhilash Padavannil,
Shan Zhang,
Sheryl Beh,
David R L Robinson,
Jana Meisterknecht,
Alfredo Cabrera-Orefice,
Timothy R Koves,
Chika Watanabe,
Miyuki Watanabe,
María Illescas,
Radiance Lim,
Jordan M Johnson,
Shuxun Ren,
Ya-Jun Wu,
Dennis Kappei,
Anna Maria Ghelli,
Katsuhiko Funai,
Hitoshi Osaka,
Deborah Muoio,
Cristina Ugalde,
Ilka Wittig,
David A Stroud,
James A Letts,
Lena Ho.
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 I2+III2, 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 Uqcrc1DEL:E258-D260 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.
Keywords: complex I; complex III; complex III ROS; cryo-EM structure; electron transport chain; ischemia reperfusion injury; mitohormesis; respirasome; reverse electron transport; supercomplex