Abstract
Emerging reports indicate that activated PKC isoforms that translocate to the mitochondria are pro- or anti-apoptotic to mitochondrial function. Here, we concentrate on the role of PKCβ translocated to mitochondria in relation to the fate of neurons following cerebral ischemia. As we have demonstrated previously ischemia/reperfusion injury (I/R) results in translocation of PKCβ from cytoplasm to mitochondria, but only in ischemia-resistant regions of the hippocampus (CA2-4, DG), we hypothesize that this translocation may be a mediator of a protective signaling mechanism in this region. We have therefore sought to demonstrate a possible relationship between PKCβII translocation and ischemic resistance of CA2-4, DG. Here, we reveal that I/R injury induces a marked elevation of PKCβII protein levels, and consequent enzymatic activity, in CA2-4, DG in the mitochondrial fraction. Moreover, the administration of an isozyme-selective PKCβII inhibitor showed inhibition of I/R-induced translocation of PKCβII to the mitochondria and an increase in neuronal death following I/R injury in CA1 and CA2-4, DG in both an in vivo and an in vitro model of ischemia. The present results suggest that PKCβII translocated to mitochondria is involved in providing ischemic resistance of CA2-4, DG. However, the exact mechanisms by which PKCβII-mediated neuroprotection is achieved are in need of further elucidation.
Highlights
As mitochondria are the principal mediators of the cell death that occurs during cerebral ischemia, they are important targets for neuroprotective interventions
As we have shown previously, ischemia/ reperfusion (I/R) injury induces a significant elevation of PKCβ immunoreactivity in the mitochondrial fraction, but mainly in the ischemia-resistant part of the hippocampus (CA2-4, DG) [17]
Western blots identified specific PKCβ isozymes, and revealed that it is rather PKCβII than PKCβI which increases in the mitochondrial fraction after I/R (Fig. 1c)
Summary
As mitochondria are the principal mediators of the cell death that occurs during cerebral ischemia, they are important targets for neuroprotective interventions. Recent reports indicate participation of the protein kinase C (PKC) family of serine/threonine kinases in the regulation of mitochondrial metabolism capable of determining the fate of cells following ischemic stress. Activation of multiple PKC isozymes has been shown to occur after ischemia/ reperfusion (I/R) injury, in multiple organs including the heart, liver, kidney and brain, suggesting its involvement in ischemic response pathways [1]. Simultaneous translocation of PKCs to specialized membrane compartments including mitochondria is observed. The role of individual isozymes of PKCs in ischemic injury appears rather contradictory, given that these can mediate different and sometimes opposing functions following activation by the same stimulus. Two isozymes of a novel type of PKC, PKCε and PKCδ, show opposite effects on apoptosis [2]
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