NF-κB and IκBα are found in the mitochondria -: Evidence for regulation of mitochondrial gene expression by NF-κB

The transcription factor NF-kappaB 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 IkappaB, the inhibitor of NF-kappaB, allowing nuclear accumulation of NF-kappaB and regulation of specific gene expression. The degradation of IkappaB is controlled initially by phosphorylation induced by the IkappaB kinase, which leads to ubiquitination and subsequent proteolysis of the inhibitor by the proteasome. We report here that NF-kappaB and IkappaBalpha but not IkappaBbeta are also localized in the mitochondria. Stimulation of cells with tumor necrosis factor a leads to the phosphorylation, of mitochondrial IkappaBalpha 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-kappaB by expression of the superrepressor form of IkappaBalpha inhibited the loss of expression of both cytochrome c oxidase III and cytochrome b mRNA. These data indicate that the NF-kappaB regulatory pathway exists in mitochondria and that NF-kappaB can negatively regulate mitochondrial mRNA expression.