When cells are stressed by stimuli that lead to the production of reactive oxygen species (ROS) by the mitochondria, the abundance of mitochondrial manganese-dependent superoxide dismutase (MnSOD) is increased. However, a nuclear SOD2 gene encodes this mitochondrial enzyme; thus, the mitochondria must signal to the nucleus to trigger the expression of the SOD2 gene. Storz et al. show that protein kinase D (PKD), Src, Abl, and protein kinase Cγ (PKCγ) partially translocate to the mitochondria when cells are exposed to hydrogen peroxide or to agents that inhibit the mitochondrial respiratory chain [rotenone or diphenyleneiodonium chloride (DPI), which increase mitochondrial ROS production. Furthermore, PKD phosphorylation and activity was stimulated by these conditions that produce oxidative stress. RNA interference (RNAi) to decrease PKD abundance blocked the increase in expression of SOD2 (measured by an SOD2 reporter construct) in response to mitochondrial oxidative stress. The SOD2 gene is regulated by the Forkhead transcription factor FOXO3a and by the transcription factor NF-κB. Mutation of the FOXO3a regulatory site did not inhibit SOD2 induction in response to peroxide or mitochondrial oxidative stress. However, expression of a superdominant version of the inhibitor of κBα (IκBα) blocked the increase in MnSOD abundance in response to either mitochondrial oxidative stress or activated version of Src or PKD. When PKD was depleted with RNAi, the induction of an NF-κB reporter in response to peroxide or mitochondrial oxidative stress was blocked. This pathway from the mitochondria to the nucleus through PKD was important for cell survival during periods of ROS induction. Cells in which PKD or MnSOD was depleted with RNAi showed a higher frequency of cell death in response to doses of peroxide or DPI that did not cause cell death of control cells.
P. Storz, H. Döppler, A. Toker, Protein kinase D mediates mitochondrion-to-nucleus signaling and detoxification from mitochondrial reactive oxygen species. Mol. Cell. Biol. 25, 8520-8530 (2005). [Abstract] [Full Text]