Mitochondrial protein kinase Cε (PKCε): emerging role in cardiac protection from ischaemic damage

Mitochondria mediate diverse cellular functions including energy generation and ROS (reactive oxygen species) production and contribute to signal transduction. Mitochondria are also key regulators of cell viability and play a central role in necrotic and apoptotic cell death pathways induced by cardiac ischaemia/reperfusion injury. PKC (protein kinase C) ε plays a critical role in cardioprotective signalling pathways that protect the heart from ischaemia/reperfusion. Emerging evidence suggests that the cardioprotective target of PKCε resides at the mitochondria. Proposed mitochondrial targets of PKCε include mitoKATP (mitochondrial ATP-sensitive K+ channel), components of the MPTP (mitochondrial permeability transition pore) and components of the electron transport chain. This review highlights mitochondrial targets of PKCε and their possible role in cardioprotective signalling in the setting of ischaemia/reperfusion injury. Introduction Myocardial ischaemia occurs when blood flow to the heart is impaired, such as during AMI (acute myocardial infarction) or coronary bypass surgery. Restoration of coronary blood flow (reperfusion) is a prerequisite for the survival of ischaemic myocardium. Paradoxically, reperfusion of ischaemic tissue exacerbates injury, and results in necrotic and apoptotic death of cells that were only moderately injured during the preceding ischaemic insult. The most potent known mechanism of protecting the heart from ischaemia/reperfusion is by ‘preconditioning’ the heart with brief periods of intermittent ischaemia and reperfusion prior to the sustained ischaemic event [1]. IPC (ischaemic preconditioning) initiates intracellular signalling pathways, which increase cellular resistance to ischaemia/reperfusion, thus reducing infarct size. Our laboratory previously found that activation of the PKCε [ε isoenzyme of PKC (protein kinase C)] is critical for conferring the cardioprotective phenotype of IPC. We identified isoenzyme-specific PKC activators, based on intramolecular interactions within each PKC isoenzyme, and isoenzyme-specific inhibitors, based on intermolecular interactions between each PKC isoenzyme and its respective isoenzyme-selective anchoring protein, termed RACKs (receptors for activated C-kinase), to which it binds upon activation (reviewed in [2]). We found that selective activation of PKCε confers cardiac protection, whereas selective inhibition of PKCε abolishes protection induced by IPC