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April 16th, 2025
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Weill Cornell Medicine
molecular biology
biorxiv

Submitochondrial Protein Translocation in Thermogenic Regulation

Haczeyni, F.Open in Google Scholar•Jordan, J. M.Open in Google Scholar•Stein, B. D.Open in Google Scholar•Steensels, S.Open in Google Scholar•Li, L.Open in Google Scholar•Dartigue, V.Open in Google Scholar•Sarklioglu, S.Open in Google Scholar•Qiao, J.Open in Google Scholar•Zhou, X. K.Open in Google Scholar•Dannenberg, A. J.Open in Google Scholaret al.

Mitochondria-rich brown adipocytes dissipate cellular energy as heat. Excessive nutrition or prolonged cold exposure suppress thermogenesis, but the mechanisms remain incompletely understood. Here we report that excessive cold or metabolic stress-induced proton leak into the matrix interface of mitochondrial innermembrane (IM) mobilizes 73 proteins from IM into matrix, which in turn alter mitochondrial bioenergetics. Interactome analysis indicates that key subunits of the electron transport chain and the mitochondrial calcium uniporter provide histidine-rich IM docking sites for 40 translocating proteins via pH-dependent protein-protein interactions. We further determine that 34% of translocating proteins correlate with obesity in human subcutaneous adipose tissue among which the top factor, acyl-CoA thioesterase 9 (ACOT9), enzymatically deactivates and prevents the utilization of acetyl-CoA in thermogenesis and promotes obesity. Overall, this study introduces stress-induced submitochondrial protein translocation as a new mitochondrial mechanism.

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