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

Activation of protein ki- nase Ce (PKCe), opening of mitochondrial AlP-sensitive K~ chan- nels (mitoKA-rp), and increased mitochondrial reactive oxygen specie~ (ROS) are key events in the signaling that underlies cardioprotection We showed previously that mitoKATP is opened by activation of mitochondrial PKCe, designated PKCeI, that is closely associatec with mitoKATP. mitoKA-rp opening then causes an increase in ROS production by complex I of the respiratory chain. This ROS activates a second pool of PKCe, designated PKCe2, which inhibits the mito- chondrial permeability transition (MPT). In the present study, wc measured mitoKATP-dependent changes in mitochondrial matrix vol- ume to further investigate the relationships among PKCe, mitoKATP, ROS, and MPT. We present evidence that I) mitoKATP can be openec by H202 and nitric oxide (NO) and that these effects are mediated b) PKCcI and not by direct actions on mitoKATP, 2) superoxide has nc effect on mitoKATP opening, 3) exogenous H2O2 or NO also inhibit~ MPT opening, and both compounds do so independently of mitoKA-rF activity via activation of PKCe2, 4) mitoKA-rP opening induced b~, PKG, phorbol ester, or diazoxide is not mediated by ROS, anc 5) mitoKATP-generated ROS activates PKCeI and induces phospho- rylation-dependent mitoKATP opening in vitro and in vivo. Thia mitoKATP-dependent mitoKATP opening constitutes a positive feed- back loop capable of maintaining the channel open after the stimulia is no longer present. This feedback pathway may be responsible foi the lasting protective effect of preconditioning, colloquially known a~ the memory effect. [ABSTRACT FROM AUTHOR]