NF-kappa B and I kappa B alpha are found in the mitochondria. Evidence for regulation of mitochondrial gene expression by NF-kappa B.
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.
Cogswell
Patricia C
PC
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7295, USA.
Kashatus
David F
DF
Keifer
Jayne A
JA
Guttridge
Denis C
DC
Reuther
Julie Y
JY
Bristow
Cindy
C
Roy
Sophie
S
Nicholson
Donald W
DW
Baldwin
Albert S
AS
D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D020672:I-kappa B Proteins / Q000032:analysis* / Q000235:genetics; D007150:Immunohistochemistry; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure*; D008930:Mitochondria, Liver / Q000378:metabolism / Q000648:ultrastructure*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020298:U937 Cells
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606206:Nfkbia protein, rat; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha