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Elevated Na is a dynamic and reversible modulator of mitochondrial metabolism in the heart

Author

Listed:
  • Yu Jin Chung

    (King’s College)

  • Zoe Hoare

    (King’s College)

  • Friedrich Baark

    (King’s College London)

  • Chak Shun Yu

    (University of Cambridge)

  • Jia Guo

    (University Medical Centre)

  • William Fuller

    (University of Glasgow)

  • Richard Southworth

    (King’s College London)

  • Doerthe M. Katschinski

    (University Medical Centre)

  • Michael P. Murphy

    (University of Cambridge)

  • Thomas R. Eykyn

    (King’s College London)

  • Michael J. Shattock

    (King’s College)

Abstract

Elevated intracellular sodium Nai adversely affects mitochondrial metabolism and is a common feature of heart failure. The reversibility of acute Na induced metabolic changes is evaluated in Langendorff perfused rat hearts using the Na/K ATPase inhibitor ouabain and the myosin-uncoupler para-aminoblebbistatin to maintain constant energetic demand. Elevated Nai decreases Gibb’s free energy of ATP hydrolysis, increases the TCA cycle intermediates succinate and fumarate, decreases ETC activity at Complexes I, II and III, and causes a redox shift of CoQ to CoQH2, which are all reversed on lowering Nai to baseline levels. Pseudo hypoxia and stabilization of HIF-1α is observed despite normal tissue oxygenation. Inhibition of mitochondrial Na/Ca-exchange with CGP-37517 or treatment with the mitochondrial ROS scavenger MitoQ prevents the metabolic alterations during Nai elevation. Elevated Nai plays a reversible role in the metabolic and functional changes and is a novel therapeutic target to correct metabolic dysfunction in heart failure.

Suggested Citation

  • Yu Jin Chung & Zoe Hoare & Friedrich Baark & Chak Shun Yu & Jia Guo & William Fuller & Richard Southworth & Doerthe M. Katschinski & Michael P. Murphy & Thomas R. Eykyn & Michael J. Shattock, 2024. "Elevated Na is a dynamic and reversible modulator of mitochondrial metabolism in the heart," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48474-z
    DOI: 10.1038/s41467-024-48474-z
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    References listed on IDEAS

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    1. Dunja Aksentijević & Anja Karlstaedt & Marina V. Basalay & Brett A. O’Brien & David Sanchez-Tatay & Seda Eminaga & Alpesh Thakker & Daniel A. Tennant & William Fuller & Thomas R. Eykyn & Heinrich Taeg, 2020. "Intracellular sodium elevation reprograms cardiac metabolism," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    2. Edward T. Chouchani & Victoria R. Pell & Edoardo Gaude & Dunja Aksentijević & Stephanie Y. Sundier & Ellen L. Robb & Angela Logan & Sergiy M. Nadtochiy & Emily N. J. Ord & Anthony C. Smith & Filmon Ey, 2014. "Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS," Nature, Nature, vol. 515(7527), pages 431-435, November.
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