| 17513497 |
Heinen A, Aldakkak M, Stowe DF, Rhodes SS, Riess ML, Varadarajan SG, Camara AK: Reverse electron flow-induced ROS production is attenuated by activation of mitochondrial Ca2+-sensitive K+ channels. J Appl Physiol. 2007 Aug;103(2):623-8. Epub 2007 Apr 26.
Mitochondria generate reactive oxygen species (ROS) dependent on substrate conditions, O (2) concentration, redox state, and activity of the mitochondrial complexes. It is well known that the FADH (2)-linked substrate succinate induces reverse electron flow to complex I of the electron transport chain and that this process generates superoxide (O (2)(*-)); these effects are blocked by the complex I blocker rotenone. We demonstrated recently that succinate + rotenone-dependent H (2) O (2) production in isolated mitochondria increased mildly on activation of the putative big mitochondrial Ca (2+)-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 O (2) consumption, membrane potential (DeltaPsi (m)), H (2) O (2) release rates, and redox state in isolated guinea pig heart mitochondria respiring on succinate but without rotenone. NS-1619 (30 microM) 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 microM). Paxilline alone had no effect on respiration. NS-1619 did not alter DeltaPsi (m) or redox state but decreased H (2) O (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 (+) influx through mtBK (Ca) channels reduces mitochondrial H (2) O (2) production by accelerating forward electron flow. Our prior study showed that NS-1619 induced an increase in H (2) O (2) 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. |
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