한빛사논문
Young-Cheul Shin,1,2,9 Pedro Latorre-Muro,2,3,9,* Amina Djurabekova,4,10 Oleksii Zdorevskyi,4,10 Christopher F. Bennett,2,3 Nils Burger,2,3 Kangkang Song,5,6 Chen Xu,5,6 Joao A. Paulo,2 Steven P. Gygi,2 Vivek Sharma,4,7 Maofu Liao,1,8,* and Pere Puigserver 2,3,11,*
1Department of Chemical Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
2Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
3Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
4Department of Physics, University of Helsinki, Helsinki 00014, Finland
5Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA
6Cryo-EM Core Facility, University of Massachusetts Medical School, Worcester, MA 01605, USA
7HiLIFE Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland
8Institute for Biological Electron Microscopy, Southern University of Science and Technology, Shenzhen, China
9These authors contributed equally
10These authors contributed equally
11Lead contact
*Corresponding authors: correspondence to Pedro Latorre-Muro, Maofu Liao or Pere Puigserver
Abstract
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.
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