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H+ transport is an integral function of the mitochondrial ADP/ATP carrier

Author

Listed:
  • Ambre M. Bertholet

    (University of California San Francisco)

  • Edward T. Chouchani

    (Harvard Medical School)

  • Lawrence Kazak

    (Harvard Medical School)

  • Alessia Angelin

    (University of Pennsylvania)

  • Andriy Fedorenko

    (University of California San Francisco)

  • Jonathan Z. Long

    (Harvard Medical School)

  • Sara Vidoni

    (Harvard Medical School)

  • Ryan Garrity

    (Harvard Medical School)

  • Joonseok Cho

    (University of Florida College of Medicine)

  • Naohiro Terada

    (University of Florida College of Medicine)

  • Douglas C. Wallace

    (University of Pennsylvania)

  • Bruce M. Spiegelman

    (Harvard Medical School)

  • Yuriy Kirichok

    (University of California San Francisco)

Abstract

The mitochondrial ADP/ATP carrier (AAC) is a major transport protein of the inner mitochondrial membrane. It exchanges mitochondrial ATP for cytosolic ADP and controls cellular production of ATP. In addition, it has been proposed that AAC mediates mitochondrial uncoupling, but it has proven difficult to demonstrate this function or to elucidate its mechanisms. Here we record AAC currents directly from inner mitochondrial membranes from various mouse tissues and identify two distinct transport modes: ADP/ATP exchange and H+ transport. The AAC-mediated H+ current requires free fatty acids and resembles the H+ leak via the thermogenic uncoupling protein 1 found in brown fat. The ADP/ATP exchange via AAC negatively regulates the H+ leak, but does not completely inhibit it. This suggests that the H+ leak and mitochondrial uncoupling could be dynamically controlled by cellular ATP demand and the rate of ADP/ATP exchange. By mediating two distinct transport modes, ADP/ATP exchange and H+ leak, AAC connects coupled (ATP production) and uncoupled (thermogenesis) energy conversion in mitochondria.

Suggested Citation

  • Ambre M. Bertholet & Edward T. Chouchani & Lawrence Kazak & Alessia Angelin & Andriy Fedorenko & Jonathan Z. Long & Sara Vidoni & Ryan Garrity & Joonseok Cho & Naohiro Terada & Douglas C. Wallace & Br, 2019. "H+ transport is an integral function of the mitochondrial ADP/ATP carrier," Nature, Nature, vol. 571(7766), pages 515-520, July.
    • Handle: RePEc:nat:nature:v:571:y:2019:i:7766:d:10.1038_s41586-019-1400-3
    DOI: 10.1038/s41586-019-1400-3
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    Cited by:

    1. Chen, Shuxian & Dai, Xiaohu & Yang, Donghai & Dai, Lingling & Hua, Yu, 2023. "Enhancing PHA production through metal-organic frameworks: Mechanisms involving superproton transport and bacterial metabolic pathways," Applied Energy, Elsevier, vol. 348(C).
    2. 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.
    3. Xiaoting Sun & Wenhai Sui & Zepeng Mu & Sisi Xie & Jinxiu Deng & Sen Li & Takahiro Seki & Jieyu Wu & Xu Jing & Xingkang He & Yangang Wang & Xiaokun Li & Yunlong Yang & Ping Huang & Minghua Ge & Yihai , 2023. "Mirabegron displays anticancer effects by globally browning adipose tissues," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    4. Erminia Donnarumma & Michael Kohlhaas & Elodie Vimont & Etienne Kornobis & Thibault Chaze & Quentin Giai Gianetto & Mariette Matondo & Maryse Moya-Nilges & Christoph Maack & Timothy Wai, 2022. "Mitochondrial Fission Process 1 controls inner membrane integrity and protects against heart failure," Nature Communications, Nature, vol. 13(1), pages 1-24, December.

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