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Mitochondrial uncouplers induce proton leak by activating AAC and UCP1

Author

Listed:
  • Ambre M. Bertholet

    (University of California San Francisco
    University of California Los Angeles)

  • 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)

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.

Suggested Citation

  • Ambre M. Bertholet & Andrew M. Natale & Paola Bisignano & Junji Suzuki & Andriy Fedorenko & James Hamilton & Tatiana Brustovetsky & Lawrence Kazak & Ryan Garrity & Edward T. Chouchani & Nickolay Brust, 2022. "Mitochondrial uncouplers induce proton leak by activating AAC and UCP1," Nature, Nature, vol. 606(7912), pages 180-187, June.
    • Handle: RePEc:nat:nature:v:606:y:2022:i:7912:d:10.1038_s41586-022-04747-5
    DOI: 10.1038/s41586-022-04747-5
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    Cited by:

    1. Antoine Gagelin & Corentin Largeau & Sandrine Masscheleyn & Mathilde S. Piel & Daniel Calderón-Mora & Frédéric Bouillaud & Jérôme Hénin & Bruno Miroux, 2023. "Molecular determinants of inhibition of UCP1-mediated respiratory uncoupling," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Jacqueline A. Turner & Malia A. Fredrickson & Marc D’Antonio & Elizabeth Katsnelson & Morgan MacBeth & Robert Gulick & Tugs-Saikhan Chimed & Martin McCarter & Angelo D’Alessandro & William A. Robinson, 2023. "Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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