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08 Disruption of hexokinase II-mitochondrial binding affects cardiac oxygen consumption and lactate production in the beating heart
  1. R Nederlof1,
  2. E Gürel1,
  3. A Koeman1,
  4. M W Hollmann1,
  5. R Southworth2,
  6. C J Zuurbier1
  1. 1Department of Anaesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  2. 2Division of Imaging Sciences, King's College, London, UK

Abstract

Background The glycolytic enzyme hexokinase (HK) is located either in the cytosol or bound to mitochondria (mitoHK). We recently demonstrated that a decrease in mitoHK increased cardiac ischaemia (I)-reperfusion (R) injury and cardiac remodelling, and prevented ischaemic preconditioning. However, the physiological implication of HK binding to mitochondria is unknown.

Hypothesis In the present study we hypothesise that mitoHK affects cardiac oxygen consumption (MVO2) and glycolysis-glucose oxidation coupling (lactate efflux).

Methods and Results Isolated Langendorff perfused rat hearts (substrate 10 mM glucose) were treated 20 min with saline (control group 1), 1 μM TAT only (control group 2), 200 nM TAT-HKII or 1 μM TAT- HKII, followed by 15 min I and 30 min R. TAT-HKII peptide contains the binding motif of HKII with mitochondria and was shown to displace HKII from mitochondria. MVO2 and lactate efflux were measured during peptide treatment. Low-dose TAT-HK reduced cardiac MVO2 by approximately 10%. High-dose TAT-HK only transiently reduced MVO2, with increased MVO2 at the end of peptide treatment. Effluent lactate concentration increased dose-dependently with TAT-HK peptide treatment from 0.02 to 0.03 mM (control groups) to 0.06 mM (200 nM TAT-HK) and 0.09 mM (1 μM TAT-HK). No cell necrosis was observed in both control groups following IR. However, TAT-HK treatment dose-dependently increased cell necrosis. Peptide treatment was not associated with changes in MDA or aconitase activity.

Conclusions This study shows for the first time that mitoHK affects cardiac MVO2. In addition, our data suggest that mitoHK may also determine glycolysis-glucose oxidation coupling.

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Footnotes

  • Funding Supported by Netherlands Heart Foundation (NHS 2010B011).

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