TY - JOUR
T1 - Acute detachment of hexokinase II from mitochondria modestly increases oxygen consumption of the intact mouse heart
AU - Nederlof, Rianne
AU - Denis, Simone
AU - Lauzier, Benjamin
AU - Rosiers, Christine Des
AU - Laakso, Markku
AU - Hagen, Jacob
AU - Argmann, Carmen
AU - Wanders, Ronald
AU - Houtkooper, Riekelt H.
AU - Hollmann, Markus W.
AU - Houten, Sander M.
AU - Zuurbier, Coert J.
PY - 2017
Y1 - 2017
N2 - 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. 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. These results indicate that acute albeit not chronic changes in mitochondrial HKII modestly affect cardiac oxygen consumption and energy substrate metabolism
AB - 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. 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. These results indicate that acute albeit not chronic changes in mitochondrial HKII modestly affect cardiac oxygen consumption and energy substrate metabolism
U2 - https://doi.org/10.1016/j.metabol.2017.04.008
DO - https://doi.org/10.1016/j.metabol.2017.04.008
M3 - Article
C2 - 28641785
SN - 0026-0495
VL - 72
SP - 66
EP - 74
JO - Metabolism: clinical and experimental
JF - Metabolism: clinical and experimental
ER -