Intramitochondrial signaling: interactions among mitoKATP, PKCepsilon, ROS, and MPT.
Activation of protein kinase Cepsilon (PKCepsilon), opening of mitochondrial ATP-sensitive K(+) channels (mitoK(ATP)), and increased mitochondrial reactive oxygen species (ROS) are key events in the signaling that underlies cardioprotection. We showed previously that mitoK(ATP) is opened by activation of a mitochondrial PKCepsilon, designated PKCepsilon1, that is closely associated with mitoK(ATP). mitoK(ATP) opening then causes an increase in ROS production by complex I of the respiratory chain. This ROS activates a second pool of PKCepsilon, designated PKCepsilon2, which inhibits the mitochondrial permeability transition (MPT). In the present study, we measured mitoK(ATP)-dependent changes in mitochondrial matrix volume to further investigate the relationships among PKCepsilon, mitoK(ATP), ROS, and MPT. We present evidence that 1) mitoK(ATP) can be opened by H(2)O(2) and nitric oxide (NO) and that these effects are mediated by PKCepsilon1 and not by direct actions on mitoK(ATP), 2) superoxide has no effect on mitoK(ATP) opening, 3) exogenous H(2)O(2) or NO also inhibits MPT opening, and both compounds do so independently of mitoK(ATP) activity via activation of PKCepsilon2, 4) mitoK(ATP) opening induced by PKG, phorbol ester, or diazoxide is not mediated by ROS, and 5) mitoK(ATP)-generated ROS activates PKCepsilon1 and induces phosphorylation-dependent mitoK(ATP) opening in vitro and in vivo. Thus mitoK(ATP)-dependent mitoK(ATP) 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.
Costa
Alexandre D T
AD
Dept. of Biology, Portland State Univ., PO Box 751, Portland, OR 97201-0751, USA.
Garlid
Keith D
KD
D000818:Animals; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology; D004789:Enzyme Activation; D025461:Feedback, Physiological; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006861:Hydrogen Peroxide / Q000378:metabolism; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000201:enzymology; D000083162:Mitochondrial Permeability Transition Pore; D053142:Mitochondrial Size; D009569:Nitric Oxide / Q000378:metabolism; D010766:Phosphorylation; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors
D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D015221:Potassium Channels; D017382:Reactive Oxygen Species; C117780:mitochondrial K(ATP) channel; D013481:Superoxides; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; C497257:Prkce protein, rat; D000071679:Glycogen Synthase Kinase 3 beta; D017869:Cyclic GMP-Dependent Protein Kinases; D051744:Protein Kinase C-epsilon; D038362:Glycogen Synthase Kinase 3; D013755:Tetradecanoylphorbol Acetate; D003981:Diazoxide