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1 Anesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2 Physiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
3 Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
* To whom correspondence should be addressed. E-mail: c.j.zuurbier{at}amc.uva.nl.
Association of hexokinase with mitochondria preserves mitochondrial integrity and is an important mechanism by which cancer cells are protected against hypoxic conditions. Maintenance of mitochondrial integrity also figures prominently as a major characteristic of many cardioprotective manipulations. In this study, we provide evidence that cardioprotective interventions may promote hexokinase redistribution from the cytosol to the mitochondria in the heart. Isolated Langendorff-perfused rat hearts (n=6 each group) were either subjected to normoxic perfusion (control, CON), three 5-min ischemia-reperfusion periods (ischemic preconditioning, IPC), 1 U/l insulin (INS) or 10 µM morphine (MOR). Hearts were immediately homogenized and centrifuged to obtain whole-cell and cytosolic fractions. Hexokinase (HK), lactate dehydrogenase (LDH) and citrate synthase (CS) enzyme activities were determined in both fractions. No change in LDH or CS present in the cytosol fraction relative to whole-cell was observed with any of the cardioprotective interventions. By contrast, HK present in the cytosol fraction relative to whole-cell activity decreased significantly (p<0.05) with all cardioprotective interventions from 0.58 ± 0.03 (CON) to 0.46 ± 0.04 (IPC), 0.41 ± 0.01 (INS) and 0.45 ± 0.02 (MOR). In addition, HK relative to CS activity in the mitochndrial fraction increased significantly with cardioprotection from 0.15 ± 0.001 (CON) to 0.21 ± 0.002 (IPC), 0.18 ± 0.003 (INS) and 0.21 ± 0.005 (MOR).Our novel data suggest that well-known cardioprotective interventions share a common end-effector mechanism of cytosolic HK translocation. Association of HK with the mitochondria may promote inhibition of the mitochondrial permeability transition pore and thereby reduce cell death and apoptosis.
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