Reverse electron flow-induced ROS production is attenuated by activation of mitochondrial Ca super(2+)-sensitive K super(+) channels

Mitochondria generate reactive oxygen species (ROS) dependent on substrate conditions, O sub(2) concentration, redox state, and activity of the mitochondrial complexes. It is well known that the FADH sub(2)-linked substrate succinate induces reverse electron flow to complex I of the electron transpo...

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Veröffentlicht in:American Journal of Physiology: Cell Physiology 2007-09, Vol.293 (3), p.H1400-H1407
Hauptverfasser: Heinen, Andre, Aldakkak, Mohammed, Stowe, David F, Rhodes, Samhita S, Riess, Matthias L, Varadarajan, Srinivasan G, Camara, Amadou KS
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Sprache:eng
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Zusammenfassung:Mitochondria generate reactive oxygen species (ROS) dependent on substrate conditions, O sub(2) concentration, redox state, and activity of the mitochondrial complexes. It is well known that the FADH sub(2)-linked substrate succinate induces reverse electron flow to complex I of the electron transport chain and that this process generates superoxide (O sub(2) super({bullet}-)); these effects are blocked by the complex I blocker rotenone. We demonstrated recently that succinate + rotenone-dependent H sub(2)O sub(2) production in isolated mitochondria increased mildly on activation of the putative big mitochondrial Ca super(2+)-sensitive K super(+) channel (mtBK sub(Ca)) by low concentrations of 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluorome t hyl)-2H-benzimidazol-2-one (NS-1619). In the present study we examined effects of NS-1619 on mitochondrial O sub(2) consumption, membrane potential ( Delta psi sub(m)), H sub(2)O sub(2) release rates, and redox state in isolated guinea pig heart mitochondria respiring on succinate but without rotenone. NS-1619 (30 mu M) increased state 2 and state 4 respiration by 26 plus or minus 4% and 14 plus or minus 4%, respectively; this increase was abolished by the BK sub(Ca) channel blocker paxilline (5 mu M). Paxilline alone had no effect on respiration. NS-1619 did not alter Delta psi sub(m) or redox state but decreased H sub(2)O sub(2) 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 super(+) influx through mtBK sub(Ca) channels reduces mitochondrial H sub(2)O sub(2) production by accelerating forward electron flow. Our prior study showed that NS-1619 induced an increase in H sub(2)O sub(2) production with blocked reverse electron flow. The present results suggest that NS-1619-induced matrix K super(+) 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.
ISSN:0363-6143
1522-1563