HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 293/3/H1400    most recent 00198.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Heinen, A. Articles by Camara, A. K. S. Search for Related Content PubMed PubMed Citation Articles by Heinen, A. Articles by Camara, A. K. S.

Reverse electron flow-induced ROS production is attenuated by activation of mitochondrial Ca²⁺-sensitive K⁺ channels

Anesthesiology Research Laboratories, Departments of ¹Anesthesiology and ²Physiology and ³Cardiovascular Research Center, Medical College of Wisconsin, ⁴Zablocki Department of Veterans Affairs Medical Center Research Service, and ⁵Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin; and ⁶Laboratory of Experimental Intensive Care and Anesthesiology, University of Amsterdam, Amsterdam, the Netherlands

Submitted 14 February 2007 ; accepted in final form 13 May 2007

Mitochondria generate reactive oxygen species (ROS) dependent on substrate conditions, O₂ concentration, redox state, and activity of the mitochondrial complexes. It is well known that the FADH₂-linked substrate succinate induces reverse electron flow to complex I of the electron transport chain and that this process generates superoxide (O₂^–); these effects are blocked by the complex I blocker rotenone. We demonstrated recently that succinate + rotenone-dependent H₂O₂ production in isolated mitochondria increased mildly on activation of the putative big mitochondrial Ca²⁺-sensitive K⁺ channel (mtBK_Ca) by low concentrations of 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one (NS-1619). In the present study we examined effects of NS-1619 on mitochondrial O₂ consumption, membrane potential (_m), H₂O₂ release rates, and redox state in isolated guinea pig heart mitochondria respiring on succinate but without rotenone. NS-1619 (30 µM) increased state 2 and state 4 respiration by 26 ± 4% and 14 ± 4%, respectively; this increase was abolished by the BK_Ca channel blocker paxilline (5 µM). Paxilline alone had no effect on respiration. NS-1619 did not alter _m or redox state but decreased H₂O₂ production by 73% vs. control; this effect was incompletely inhibited by paxilline. We conclude that under substrate conditions that allow reverse electron flow, matrix K⁺ influx through mtBK_Ca channels reduces mitochondrial H₂O₂ production by accelerating forward electron flow. Our prior study showed that NS-1619 induced an increase in H₂O₂ production with blocked reverse electron flow. The present results suggest that NS-1619-induced matrix K⁺ influx increases forward electron flow despite the high reverse electron flow, and emphasize the importance of substrate conditions on interpretation of effects on mitochondrial bioenergetics.

mitochondria; reactive oxygen species; potassium channels