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Targeting of Protein Kinase C to Mitochondria in the Oxidative Stress Response¹

Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 [P. K. M., X. S., A. B., S. K., D. K.] and Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87115 [N. C. M., S. S.]

The cellular response to oxidative stress includes the release of mitochondrial cytochrome c and the induction of apoptosis. Here we show that treatment of diverse cells with hydrogen peroxide (H₂O₂) induces the targeting of protein kinase C (PKC) to mitochondria. The results demonstrate that H₂O₂-induced activation of PKC is necessary for translocation of PKC from the cytoplasm to the mitochondria. The results also show that mitochondrial targeting of PKC is associated with the loss of mitochondrial transmembrane potential and release of cytochrome c. The functional importance of this event is also supported by the demonstration that H₂O₂-induced apoptosis is blocked by the inhibition of PKC activation and translocation to mitochondria. These findings indicate that mitochondrial targeting of PKC is required, at least in part, for the apoptotic response of cells to oxidative stress.

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