Mitochondrial uncouplers induce proton leak by activating AAC and UCP1

Ambre M. Bertholet, Andrew M. Natale, Paola Bisignano, Junji Suzuki, Andriy Fedorenko, James Hamilton, Tatiana Brustovetsky, Lawrence Kazak, Ryan Garrity, Edward T. Chouchani, Nickolay Brustovetsky, Michael Grabe () and Yuriy Kirichok ()
Additional contact information
Ambre M. Bertholet: University of California San Francisco
Andrew M. Natale: University of California San Francisco
Paola Bisignano: University of California San Francisco
Junji Suzuki: University of California San Francisco
Andriy Fedorenko: University of California San Francisco
James Hamilton: Indiana University
Tatiana Brustovetsky: Indiana University
Lawrence Kazak: Harvard Medical School
Ryan Garrity: Harvard Medical School
Edward T. Chouchani: Harvard Medical School
Nickolay Brustovetsky: Indiana University
Michael Grabe: University of California San Francisco
Yuriy Kirichok: University of California San Francisco

Nature, 2022, vol. 606, issue 7912, 180-187

Abstract: Abstract Mitochondria generate heat due to H+ leak (IH) across their inner membrane1. IH results from the action of long-chain fatty acids on uncoupling protein 1 (UCP1) in brown fat2–6 and ADP/ATP carrier (AAC) in other tissues1,7–9, but the underlying mechanism is poorly understood. As evidence of pharmacological activators of IH through UCP1 and AAC is lacking, IH is induced by protonophores such as 2,4-dinitrophenol (DNP) and cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP)10,11. Although protonophores show potential in combating obesity, diabetes and fatty liver in animal models12–14, their clinical potential for treating human disease is limited due to indiscriminately increasing H+ conductance across all biological membranes10,11 and adverse side effects15. Here we report the direct measurement of IH induced by DNP, FCCP and other common protonophores and find that it is dependent on AAC and UCP1. Using molecular structures of AAC, we perform a computational analysis to determine the binding sites for protonophores and long-chain fatty acids, and find that they overlap with the putative ADP/ATP-binding site. We also develop a mathematical model that proposes a mechanism of uncoupler-dependent IH through AAC. Thus, common protonophoric uncouplers are synthetic activators of IH through AAC and UCP1, paving the way for the development of new and more specific activators of these two central mediators of mitochondrial bioenergetics.

Date: 2022
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DOI: 10.1038/s41586-022-04747-5

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