Elevated Na is a dynamic and reversible modulator of mitochondrial metabolism in the heart.
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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.
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Acknowledgements: This work was supported by British Heart Foundation Programme Grant RG/12/4/29426 and RG/17/15/33106 (M.J.S. and W.F.); NIHR Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and KCL (T.R.E. and R.S.); EPSRC Programme grants “MITHRAS” EP/S032789/1 and “RedOx-KCL” EP/S019901/1 (R.S. and F.B.); German Research Foundation GRK2824 and KA1269/13-1 (J.G. and D.M.K.); Medical Research Council UK (MC_UU_00028/4); Wellcome Trust Investigator award 220257/Z/20/Z (M.P.M.); the Centre of Excellence in Medical Engineering funded by the Wellcome Trust and Engineering and EPSRC WT 203148/Z/16/Z (T.R.E. and R.S.) and the BHF Centre of Research Excellence RE/18/2/34213. We thank Dr Mufassra Mushtaq (University Medical Centre Göttingen, Germany) for technical assistance in myocyte preparation for the MitoSox experiments.
Funder: NIHR Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and KCL
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2041-1723
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MRC (MC_UU_00028/4)