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Regulatory interaction between metabolite transporters coordinates glucose and exometabolite fluxes to drive bioenergetics

Author

Listed:
  • Noa Yehoshua

    (Ben Gurion University of the Negev)

  • Ahlam Khamaysi

    (Ben Gurion University of the Negev)

  • Liana Shimshilashvili

    (Ben Gurion University of the Negev)

  • Aharon Keshet

    (Ben Gurion University of the Negev)

  • Mahmoud Taha

    (Ben Gurion University of the Negev)

  • Moran Fremder

    (Ben Gurion University of the Negev)

  • Hadar Eini-Rider

    (Ben Gurion University of the Negev)

  • Ehud Ohana

    (Ben Gurion University of the Negev
    Ben Gurion University of the Negev)

Abstract

The composition of tricarboxylic acid cycle metabolites in the external environment of cells determines vital physiological functions, including nutrient and mineral absorption, inflammation, and cellular energy management. Here, we study how the transport of external metabolites into the cells functions as an independent metabolic pathway that controls cellular energy. We show that liver cells orchestrate simultaneous fluxes of glucose and the omnipotent metabolite citrate across the cell membrane, acting as a first line metabolic pathway that responds to nutrient availability. Using functional mapping and gene silencing, we delineate the underlying molecular mechanism showing that the liver citrate transporter (NaCT) interacts with glucose transporters (Glut) and the anion transporters. The interaction is mediated by a specific region of the NaCT protein to reciprocally regulate the transport functions. Our findings describe an independent mechanism that coordinates external metabolites and glucose balance, thus driving key energy management processes in response to nutrient availability in the liver.

Suggested Citation

  • Noa Yehoshua & Ahlam Khamaysi & Liana Shimshilashvili & Aharon Keshet & Mahmoud Taha & Moran Fremder & Hadar Eini-Rider & Ehud Ohana, 2025. "Regulatory interaction between metabolite transporters coordinates glucose and exometabolite fluxes to drive bioenergetics," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62103-3
    DOI: 10.1038/s41467-025-62103-3
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    References listed on IDEAS

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    1. David B. Sauer & Jinmei Song & Bing Wang & Jacob K. Hilton & Nathan K. Karpowich & Joseph A. Mindell & William J. Rice & Da-Neng Wang, 2021. "Structure and inhibition mechanism of the human citrate transporter NaCT," Nature, Nature, vol. 591(7848), pages 157-161, March.
    2. David B. Sauer & Jennifer J. Marden & Joseph C. Sudar & Jinmei Song & Christopher Mulligan & Da-Neng Wang, 2022. "Structural basis of ion – substrate coupling in the Na+-dependent dicarboxylate transporter VcINDY," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    3. Ernest Turro & William J. Astle & Karyn Megy & Stefan Gräf & Daniel Greene & Olga Shamardina & Hana Lango Allen & Alba Sanchis-Juan & Mattia Frontini & Chantal Thys & Jonathan Stephens & Rutendo Mapet, 2020. "Whole-genome sequencing of patients with rare diseases in a national health system," Nature, Nature, vol. 583(7814), pages 96-102, July.
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