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Intramitochondrial signaling: interactions among mitoK ATP , PKCε, ROS, and MPT

2008; American Physical Society; Volume: 295; Issue: 2 Linguagem: Inglês

10.1152/ajpheart.01189.2007

1522-1539

Alexandre Dias Tavares Costa, Keith Garlid,

Cardiac Arrest and Resuscitation

Activation of protein kinase Cε (PKCε), 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 PKCε, designated PKCε1, 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 PKCε, designated PKCε2, 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 PKCε, 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 PKCε1 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 PKCε2, 4) mitoK ATP opening induced by PKG, phorbol ester, or diazoxide is not mediated by ROS, and 5) mitoK ATP -generated ROS activates PKCε1 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.