Elevated Na is a dynamic and reversible modulator of mitochondrial metabolism in the heart: Intracellular Na reversibly alters myocardial metabolism and energetics

Yu Jin Chung, Zoe Hoare, Friedrich Baark, Chat Shun Yu, Jia Gun, William Fuller, Richard Southworth, Dörthe M. Katschinski, Michael P. Murphy, Thomas Eykyn, Michael Shattock*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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 was 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 decreased Gibb’s free energy of ATP hydrolysis, increased the TCA cycle intermediates succinate and fumarate, decreased ETC activity at Complexes I, II and III, and caused a redox shift of CoQ to CoQH2, which were all reversed on lowering Nai to baseline levels. Pseudo hypoxia and stabilization of HIF-1 was observed despite normal tissue oxygenation. Inhibition of mitochondrial Na/Ca-exchange with CGP-37517 or treatment with the mitochondrial ROS scavenger MitoQ prevented 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.
Original languageEnglish
JournalNature Communications
Publication statusAccepted/In press - 4 Apr 2024

Keywords

  • intracellular sodium
  • mitochondrial metabolism
  • reactive oxygen species
  • oxidative stress
  • pseudohypoxia
  • nuclear magnetic resonance spectroscopy
  • heart failure

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