EMD-42138
CI protomer-1 peripheral arm focus refined map
EMD-42138
Single-particle3.72 Å
Deposition: 27/09/2023Map released: 22/01/2025
Last modified: 19/02/2025
Sample Organism:
Mus musculus
Sample: Mitochondrial Super-complex with CI dimer and CIII dimer (Super-complex XL)
Deposition Authors: Letts JA, Padavannil A
Sample: Mitochondrial Super-complex with CI dimer and CIII dimer (Super-complex XL)
Deposition Authors: Letts JA, Padavannil A
Formation of I 2 +III 2 supercomplex rescues respiratory chain defects.
Liang C,
Padavannil A,
Zhang S,
Beh S,
Robinson DRL,
Meisterknecht J,
Cabrera-Orefice A,
Koves TR,
Watanabe C,
Watanabe M,
Illescas M,
Lim R,
Johnson JM,
Ren S,
Wu YJ,
Kappei D,
Ghelli AM,
Funai K,
Osaka H,
Muoio D,
Ugalde C,
Wittig I,
Stroud DA,
Letts JA,
Ho L
(2025) Cell Metab. , 37 , 441 - 459.e11
(2025) Cell Metab. , 37 , 441 - 459.e11
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 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.
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.