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

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 () and Michael J. Shattock ()
Additional contact information
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

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48474-z

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