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1 Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
2 Dept of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
3 Anesthesiology, Medical College of Wisconsin, Milwaukee, United States
* To whom correspondence should be addressed. E-mail: dfstowe{at}mcw.edu.
We recently showed a role for altered mitochondrial bioenergetics and reactive oxygen species (ROS) production in mitochondrial Ca2+ sensitive K+ (mKCa) channel opening -induced preconditioning in isolated hearts. However, the underlying mitochondrial mechanism by which mKCa channel opening causes ROS production to trigger preconditioning is unknown. We hypothesized that submaximal mK+ influx causes ROS production due to enhanced electron flow at a fully charged membrane potential (
m). To test this we measured effects of NS1619, a putative mKCa channel opener, and valinomycin, a K+ ionophore, on mitochondrial respiration, m, and ROS generation in guinea pig heart mitochondria. NS1619 (30 µM) increased states 2 and 4 respiration, respectively, by 5.2±0.9 and 7.3±0.9 nmol O2/mg protein/min with NADH linked substrate pyruvate and by 7.5±1.4 and 11.6±2.9 nmol O2/mg protein/min with FADH2 linked substrate succinate (+ rotenone); these effects were abolished by the mKCa blocker paxilline. m was not decreased by 10-30 µM NS1619 with either substrate, but H2O2 release was increased by 44.8% (65.9±2.7% by 30 µM NS1619 vs. 21.1±3.8% for time-controls) with succinate + rotenone. In contrast, NS1619 did not increase H2O2 release with pyruvate. Similar results were found for lower concentrations of valinomycin. The increase in ROS production in succinate + rotenone supported mitochondria resulted from a fully maintained m despite increased respiration, a condition capable of allowing increased electron leak. We propose that mild matrix K+ influx during states 2 and 4 increases mitochondrial respiration, while maintaining m; this allows singlet electron uptake by O2 and ROS generation.
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