NF-κB and IκBα Are Found in the Mitochondria

The transcription factor NF-kappa B has been shown to be predominantly cytoplasmically localized in the absence of an inductive signal. Stimulation of cells with inflammatory cytokines such as tumor necrosis factor alpha or interleukin-1 induces the degradation of I kappa B, the inhibitor of NF-kappa B, allowing nuclear accumulation of NF-kappa B and regulation of specific gene expression. The degradation of I kappa B is controlled initially by phosphorylation induced by the I kappa B kinase, which leads to ubiquitination and subsequent proteolysis of the inhibitor by the proteasome. We report here that NF-kappa B and I kappa B alpha (but not I kappa B beta) are also localized in the mitochondria. Stimulation of cells with tumor necrosis factor alpha leads to the phosphorylation of mitochondrial I kappa B alpha and its subsequent degradation by a nonproteasome-dependent pathway. Interestingly, expression of the mitochondrially encoded cytochrome c oxidase III and cytochrome b mRNAs were reduced by cytokine treatment of cells. Inhibition of activation of mitochondrial NF-kappa B by expression of the superrepressor form of I kappa B alpha inhibited the loss of expression of both cytochrome c oxidase III and cytochrome b mRNA. These data indicate that the NF-kappa B regulatory pathway exists in mitochondria and that NF-kappa B can negatively regulate mitochondrial mRNA expression.