Rianne Nederlof1, Simone Denis2, Benjamin Lauzier3, Christine Des Rosiers4, Markku Laakso5, Jacob Hagen6, Carmen Argmann6, Ronald Wanders2, Riekelt H Houtkooper2, Markus W Hollmann1, Sander M Houten6, Coert J Zuurbier7. 1. Laboratory of Experimental Intensive Care and Anesthesiology, Department of Anesthesiology, Academic Medical Center, Amsterdam, The Netherlands. 2. Laboratory of Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands. 3. l'institut du thorax, INSERM, CNRS, Université de Nantes, Nantes, France. 4. Montreal Heart Institute Research Center and Department of Nutrition, Université de Montréal, Montréal, Québec, Canada. 5. Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Finland. 6. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, USA. 7. Laboratory of Experimental Intensive Care and Anesthesiology, Department of Anesthesiology, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: c.j.zuurbier@amc.uva.nl.
Abstract
OBJECTIVE: Cardiac hexokinase II (HKII) can translocate between cytosol and mitochondria and change its cellular expression with pathologies such as ischemia-reperfusion, diabetes and heart failure. The cardiac metabolic consequences of these changes are unknown. Here we measured energy substrate utilization in cytosol and mitochondria using stabile isotopes and oxygen consumption of the intact perfused heart for 1) an acute decrease in mitochondrial HKII (mtHKII), and 2) a chronic decrease in total cellular HKII. METHODS/ RESULTS: We first examined effects of 200nM TAT (Trans-Activator of Transcription)-HKII peptide treatment, which was previously shown to acutely decrease mtHKII by ~30%. In Langendorff-perfused hearts TAT-HKII resulted in a modest, but significant, increased oxygen consumption, while cardiac performance was unchanged. At the metabolic level, there was a nonsignificant (p=0.076) ~40% decrease in glucose contribution to pyruvate and lactate formation through glycolysis and to mitochondrial citrate synthase flux (6.6±1.1 vs. 11.2±2.2%), and an 35% increase in tissue pyruvate (27±2 vs. 20±2pmol/mg; p=0.033). Secondly, we compared WT and HKII+/- hearts (50% chronic decrease in total HKII). RNA sequencing revealed no differential gene expression between WT and HKII+/- hearts indicating an absence of metabolic reprogramming at the transcriptional level. Langendorff-perfused hearts showed no significant differences in glycolysis (0.34±0.03μmol/min), glucose contribution to citrate synthase flux (35±2.3%), palmitate contribution to citrate synthase flux (20±1.1%), oxygen consumption or mechanical performance between WT and HKII+/- hearts. CONCLUSIONS: These results indicate that acute albeit not chronic changes in mitochondrial HKII modestly affect cardiac oxygen consumption and energy substrate metabolism.
OBJECTIVE: Cardiac hexokinase II (HKII) can translocate between cytosol and mitochondria and change its cellular expression with pathologies such as ischemia-reperfusion, diabetes and heart failure. The cardiac metabolic consequences of these changes are unknown. Here we measured energy substrate utilization in cytosol and mitochondria using stabile isotopes and oxygen consumption of the intact perfused heart for 1) an acute decrease in mitochondrial HKII (mtHKII), and 2) a chronic decrease in total cellular HKII. METHODS/ RESULTS: We first examined effects of 200nM TAT (Trans-Activator of Transcription)-HKII peptide treatment, which was previously shown to acutely decrease mtHKII by ~30%. In Langendorff-perfused hearts TAT-HKII resulted in a modest, but significant, increased oxygen consumption, while cardiac performance was unchanged. At the metabolic level, there was a nonsignificant (p=0.076) ~40% decrease in glucose contribution to pyruvate and lactate formation through glycolysis and to mitochondrial citrate synthase flux (6.6±1.1 vs. 11.2±2.2%), and an 35% increase in tissue pyruvate (27±2 vs. 20±2pmol/mg; p=0.033). Secondly, we compared WT and HKII+/- hearts (50% chronic decrease in total HKII). RNA sequencing revealed no differential gene expression between WT and HKII+/- hearts indicating an absence of metabolic reprogramming at the transcriptional level. Langendorff-perfused hearts showed no significant differences in glycolysis (0.34±0.03μmol/min), glucose contribution to citrate synthase flux (35±2.3%), palmitate contribution to citrate synthase flux (20±1.1%), oxygen consumption or mechanical performance between WT and HKII+/- hearts. CONCLUSIONS: These results indicate that acute albeit not chronic changes in mitochondrial HKII modestly affect cardiac oxygen consumption and energy substrate metabolism.
Authors: Yang Xiao; Karen Yim; Hong Zhang; Diane Bakker; Rianne Nederlof; Jan A M Smeitink; Herma Renkema; Markus W Hollmann; Nina C Weber; Coert J Zuurbier Journal: Cardiovasc Drugs Ther Date: 2021-04-29 Impact factor: 3.727
Authors: Coert J Zuurbier; Luc Bertrand; Christoph R Beauloye; Ioanna Andreadou; Marisol Ruiz-Meana; Nichlas R Jespersen; Duvaraka Kula-Alwar; Hiran A Prag; Hans Eric Botker; Maija Dambrova; Christophe Montessuit; Tuuli Kaambre; Edgars Liepinsh; Paul S Brookes; Thomas Krieg Journal: J Cell Mol Med Date: 2020-05-08 Impact factor: 5.310
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Authors: Hong Zhang; Yang Xiao; Rianne Nederlof; Diane Bakker; Pengbo Zhang; Stephen E Girardin; Markus W Hollmann; Nina C Weber; Sander M Houten; Michel van Weeghel; Richard G Kibbey; Coert J Zuurbier Journal: Front Immunol Date: 2020-12-11 Impact factor: 7.561