Mitochondrial ATP-sensitive K+ channels prevent oxidative stress, permeability transition and cell death.
Ischemia followed by reperfusion results in impairment of cellular and mitochondrial functionality due to opening of mitochondrial permeability transition pores. On the other hand, activation of mitochondrial ATP-sensitive K(+) channels (mitoK(ATP)) protects the heart against ischemic damage. This study examined the effects of mitoK(ATP) and mitochondrial permeability transition on isolated rat heart mitochondria and cardiac cells submitted to simulated ischemia and reperfusion (cyanide/aglycemia). Both mitoK(ATP) opening, using diazoxide, and the prevention of mitochondrial permeability transition, using cyclosporin A, protected against cellular damage, without additive effects. MitoK(ATP) opening in isolated rat heart mitochondria slightly decreased Ca(2+) uptake and prevented mitochondrial reactive oxygen species production, most notably in the presence of added Ca(2+). In ischemic cells, diazoxide decreased ROS generation during cyanide/aglycemia while cyclosporin A prevented oxidative stress only during simulated reperfusion. Collectively, these studies indicate that opening mitoK(ATP) prevents cellular death under conditions of ischemia/reperfusion by decreasing mitochondrial reactive oxygen species release secondary to Ca(2+) uptake, inhibiting mitochondrial permeability transition.
Facundo
Heberty T F
HT
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, São Paulo, SP 05508-900, Brazil.
de Paula
Juliana G
JG
Kowaltowski
Alicia J
AJ
D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D006321:Heart / Q000187:drug effects; D054086:KATP Channels; D008297:Male; D008929:Mitochondria, Heart / Q000502:physiology*; D009206:Myocardium / Q000166:cytology; D018384:Oxidative Stress / Q000502:physiology*; D010539:Permeability; D024661:Potassium Channels, Inwardly Rectifying / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D017382:Reactive Oxygen Species; C092520:uK-ATP-1 potassium channel; D002118:Calcium