Intramitochondrial signaling: interactions among mitoKATP, PKCε, ROS, and MPT

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Abstract
Activation of protein kinase Cε (PKCε), opening of mitochondrial ATP-sensitive K+channels (mitoKATP), and increased mitochondrial reactive oxygen species (ROS) are key events in the signaling that underlies cardioprotection. We showed previously that mitoKATPis opened by activation of a mitochondrial PKCε, designated PKCε1, that is closely associated with mitoKATP. mitoKATPopening then causes an increase in ROS production by complex I of the respiratory chain. This ROS activates a second pool of PKCε, designated PKCε2, which inhibits the mitochondrial permeability transition (MPT). In the present study, we measured mitoKATP-dependent changes in mitochondrial matrix volume to further investigate the relationships among PKCε, mitoKATP, ROS, and MPT. We present evidence that 1) mitoKATPcan be opened by H2O2and nitric oxide (NO) and that these effects are mediated by PKCε1 and not by direct actions on mitoKATP, 2) superoxide has no effect on mitoKATPopening, 3) exogenous H2O2or NO also inhibits MPT opening, and both compounds do so independently of mitoKATPactivity via activation of PKCε2, 4) mitoKATPopening induced by PKG, phorbol ester, or diazoxide is not mediated by ROS, and 5) mitoKATP-generated ROS activates PKCε1 and induces phosphorylation-dependent mitoKATPopening in vitro and in vivo. Thus mitoKATP-dependent mitoKATPopening constitutes a positive feedback loop capable of maintaining the channel open after the stimulus is no longer present. This feedback pathway may be responsible for the lasting protective effect of preconditioning, colloquially known as the memory effect.

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