Cell. 2024 Oct 03. pii: S0092-8674(24)01087-0. [Epub ahead of print]
Young-Cheul Shin,
Pedro Latorre-Muro,
Amina Djurabekova,
Oleksii Zdorevskyi,
Christopher F Bennett,
Nils Burger,
Kangkang Song,
Chen Xu,
Joao A Paulo,
Steven P Gygi,
Vivek Sharma,
Maofu Liao,
Pere Puigserver.
In response to cold, mammals activate brown fat for respiratory-dependent thermogenesis reliant on the electron transport chain. Yet, the structural basis of respiratory complex adaptation upon cold exposure remains elusive. Herein, we combined thermoregulatory physiology and cryoelectron microscopy (cryo-EM) to study endogenous respiratory supercomplexes from mice exposed to different temperatures. A cold-induced conformation of CI:III2 (termed type 2) supercomplex was identified with a ∼25° rotation of CIII2 around its inter-dimer axis, shortening inter-complex Q exchange space, and exhibiting catalytic states that favor electron transfer. Large-scale supercomplex simulations in mitochondrial membranes reveal how lipid-protein arrangements stabilize type 2 complexes to enhance catalytic activity. Together, our cryo-EM studies, multiscale simulations, and biochemical analyses unveil the thermoregulatory mechanisms and dynamics of increased respiratory capacity in brown fat at the structural and energetic level.
Keywords: CIII(2) rotation; brown adipose tissue; cellular adaptation; electron transport chain; membrane lipid remodeling; respiratory complexes