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Am J Physiol Cell Physiol 292: C148-C156, 2007. First published July 26, 2006; doi:10.1152/ajpcell.00215.2006
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SPECIAL SECTION ON SYSTEMS BIOLOGY OF THE MITOCHONDRION

Mitochondrial Ca2+-induced K+ influx increases respiration and enhances ROS production while maintaining membrane potential

André Heinen,1 Amadou K. S. Camara,1 Mohammed Aldakkak,1 Samhita S. Rhodes,1 Matthias L. Riess,1 and David F. Stowe1,2,3,4,5

Anesthesiology Research Laboratories, Departments of 1Anesthesiology and 2Physiology, 3Cardiovascular Research Center, Medical College of Wisconsin, 4Veterans Affairs Medical Center Research Service, and 5Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin

Submitted 28 April 2006 ; accepted in final form 25 July 2006

We recently demonstrated a role for altered mitochondrial bioenergetics and reactive oxygen species (ROS) production in mitochondrial Ca2+-sensitive K+ (mtKCa) channel opening-induced preconditioning in isolated hearts. However, the underlying mitochondrial mechanism by which mtKCa channel opening causes ROS production to trigger preconditioning is unknown. We hypothesized that submaximal mitochondrial K+ influx causes ROS production as a result of enhanced electron flow at a fully charged membrane potential ({Delta}{Psi}m). To test this hypothesis, we measured effects of NS-1619, a putative mtKCa channel opener, and valinomycin, a K+ ionophore, on mitochondrial respiration, {Delta}{Psi}m, and ROS generation in guinea pig heart mitochondria. NS-1619 (30 µM) increased state 2 and 4 respiration by 5.2 ± 0.9 and 7.3 ± 0.9 nmol O2·min–1·mg protein–1, respectively, with the NADH-linked substrate pyruvate and by 7.5 ± 1.4 and 11.6 ± 2.9 nmol O2·min–1·mg protein–1, respectively, with the FADH2-linked substrate succinate (+ rotenone); these effects were abolished by the mtKCa channel blocker paxilline. {Delta}{Psi}m was not decreased by 10–30 µM NS-1619 with either substrate, but H2O2 release was increased by 44.8% (65.9 ± 2.7% by 30 µM NS-1619 vs. 21.1 ± 3.8% for time controls) with succinate + rotenone. In contrast, NS-1619 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 {Delta}{Psi}m, despite increased respiration, a condition that is capable of allowing increased electron leak. We propose that mild matrix K+ influx during states 2 and 4 increases mitochondrial respiration while maintaining {Delta}{Psi}m; this allows singlet electron uptake by O2 and ROS generation.

mitochondrial bioenergetics; heart mitochondria


Address for reprint requests and other correspondence: D. F. Stowe, M4280, 8701 Watertown Plank Rd., Medical College of Wisconsin, Milwaukee, WI 53226 (e-mail: dfstowe{at}mcw.edu)




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