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, Dörthe M. Katschinski, Michael P. Murphy, Thomas R. Eykyn, Michael J. Shattock
Abstract
Abstract Elevated intracellular sodium Na i 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 Na i 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 CoQH 2 , which are all reversed on lowering Na i 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 Na i elevation. Elevated Na i plays a reversible role in the metabolic and functional changes and is a novel therapeutic target to correct metabolic dysfunction in heart failure.