Redox regulation of the mitochondrial KATP channel in cardioprotection

The mitochondrial ATP-sensitive potassium channel (mKATP) is important in the protective mechanism of ischemic preconditioning (IPC). The channel is reportedly sensitive to reactive oxygen and nitrogen species, and the aim of this study was to compare such species in parallel, to build a more comprehensive picture of mKATP regulation. mKATP activity was measured by both osmotic swelling and Tl+ flux assays, in isolated rat heart mitochondria. An isolated adult rat cardiomyocyte model of ischemia–reperfusion (IR) injury was also used to determine the role of mKATP in cardioprotection by nitroxyl. Key findings were as follows: (i) mKATP was activated by O2− and H2O2 but not other peroxides. (ii) mKATP was inhibited by NADPH. (iii) mKATP was activated by S-nitrosothiols, nitroxyl, and nitrolinoleate. The latter two species also inhibited mitochondrial complex II. (iv) Nitroxyl protected cardiomyocytes against IR injury in an mKATP-dependent manner. Overall, these results suggest that the mKATP channel is activated by specific reactive oxygen and nitrogen species, and inhibited by NADPH. The redox modulation of mKATP may be an underlying mechanism for its regulation in the context of IPC. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.

Research Highlights
► Redox regulation of the mitochondrial KATP channel is poorly understood.
► Superoxide and hydrogen peroxide activated mKATP, while reductants inhibited.
► Many reactive nitrogen species inhibited mKATP, possibly via complex II inhibition.
► NADPH appeared to inhibit mKATP via a mechanism unrelated to its redox potential.