Mitochondrial ATP-sensitive K+ channels are redox-sensitive pathways that control reactive oxygen species production.
Pharmacological mitochondrial ATP-sensitive K(+) channel (mitoK(ATP)) opening protects against ischemic damage and mimics ischemic preconditioning. However, physiological and pathological signaling events that open this channel are still not fully understood. We found that catalase, which removes H(2)O(2), is capable of reversing the beneficial effects of ischemic preconditioning but not of mitoK(ATP) agonist diazoxide. On the other hand, 2-mercaptopropionylglycine prevented cardioprotection in both cases, suggesting that this compound may present effects other than scavenging of reactive oxygen species. Indeed, 2-mercaptopropionylglycine and a second thiol-reducing agent, dithiothreitol, impair diazoxide-mediated activation of mitoK(ATP) in isolated heart mitochondria. This demonstrates that mitoK(ATP) activity is regulated by thiol redox status. Furthermore, stimulating the generation of endogenous mitochondrial reactive oxygen species or treating samples with H(2)O(2) strongly enhances mitoK(ATP) activity, in a manner probably dependent on redox sensors located in the channel's sulfonylurea receptor. We also demonstrate that mitoK(ATP) channel activity effectively prevents mitochondrial reactive oxygen release. Collectively, our results suggest that mitoK(ATP) acts as a reactive oxygen sensor that decreases mitochondrial free radical generation in response to enhanced local levels of oxidants. As a result, these channels regulate mitochondrial redox state under physiological conditions and prevent oxidative stress under pathological conditions such as ischemia/reperfusion.
Facundo
Heberty T F
HT
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.
de Paula
Juliana G
JG
Kowaltowski
Alicia J
AJ
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D008929:Mitochondria, Heart / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*
D015221:Potassium Channels; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase