| Intramitochondrial signaling: interactions among mitoKATP, PKCɛ, ROS, and MPT | |||||||||||||
Abstract | |||||||||||||
| Activation of protein kinase Cɛ (PKCɛ), 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 mitoKATP is opened by activation of a mitochondrial PKCɛ, designated PKCɛ1, that is closely associated with mitoKATP. mitoKATP opening then causes an increase in ROS production by complex I of the respiratory chain. This ROS activates a second pool of PKCɛ, designated PKCɛ2, 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 PKCɛ, mitoKATP, ROS, and MPT. We present evidence that 1) mitoKATP can be opened by H2O2 and nitric oxide (NO) and that these effects are mediated by PKCɛ1 and not by direct actions on mitoKATP, 2) superoxide has no effect on mitoKATP opening, 3) exogenous H2O2 or NO also inhibits MPT opening, and both compounds do so independently of mitoKATP activity via activation of PKCɛ2, 4) mitoKATP opening induced by PKG, phorbol ester, or diazoxide is not mediated by ROS, and 5) mitoKATP-generated ROS activates PKCɛ1 and induces phosphorylation-dependent mitoKATP opening in vitro and in vivo. Thus mitoKATP-dependent mitoKATP opening 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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