Structural basis of respiratory complex adaptation to cold temperatures

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

doi:10.1016/j.cell.2024.09.029

Structural basis of respiratory complex adaptation to cold temperatures

Cell. 2024 Oct 3:S0092-8674(24)01087-0. doi: 10.1016/j.cell.2024.09.029. Online ahead of print.

Authors

Affiliations

¹ Department of Chemical Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
² Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: pedroa_latorremuro@dfci.harvard.edu.
³ Department of Physics, University of Helsinki, Helsinki 00014, Finland.
⁴ Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁵ Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Cryo-EM Core Facility, University of Massachusetts Medical School, Worcester, MA 01605, USA.
⁶ Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
⁷ Department of Physics, University of Helsinki, Helsinki 00014, Finland; HiLIFE Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland.
⁸ Department of Chemical Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China; Institute for Biological Electron Microscopy, Southern University of Science and Technology, Shenzhen, China. Electronic address: liaomf@sustech.edu.cn.
⁹ Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: pere_puigserver@dfci.harvard.edu.

PMID: 39395414
DOI: 10.1016/j.cell.2024.09.029

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.

Keywords: CIII(2) rotation; brown adipose tissue; cellular adaptation; electron transport chain; membrane lipid remodeling; respiratory complexes.