Depletion of the mitochondrial electron transport abrogates the cytotoxic and gene-inductive effects of TNF.
Tumor necrosis factor (TNF) has cytotoxic and gene-inductive activities on several cell types. Previous studies on L929 fibrosarcoma cells have revealed that the mitochondrial electron transport system plays a key role in inducing TNF cytotoxicity, presumably by the formation of reactive oxygen intermediates (ROI). Here we report that mitochondria-derived intermediates are not only cytotoxic but, in addition, function as signal transducers of TNF-induced gene expression. The activation of NF kappa B, which fulfills an important role in TNF-induced gene transcription, could be blocked by interference with the mitochondrial electron transport system. Furthermore, antimycin A, a mitochondrial inhibitor that increases the generation of ROI, potentiated TNF-triggered NF kappa B activation. The dual role of mitochondria-derived intermediates in cytotoxicity and immediate-early gene induction of TNF was further substantiated by isolating L929 subclones which lacked a functional respiratory chain. This depletion of the mitochondrial oxidative metabolism resulted in resistance towards TNF cytotoxicity, as well as in inhibition of NF kappa B activation and interleukin-6 gene induction by TNF. These findings suggest that mitochondria are the source of second messenger molecules and serve as common mediators of the TNF-cytotoxic and gene-regulatory signaling pathways.
Schulze-Osthoff
K
K
Laboratory of Molecular Biology, University of Ghent, Belgium.
Beyaert
R
R
Vandevoorde
V
V
Haegeman
G
G
Fiers
W
W
D000818:Animals; D001483:Base Sequence; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004579:Electron Transport; D005786:Gene Expression Regulation / Q000187:drug effects; D015850:Interleukin-6 / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics; D009838:Oligodeoxyribonucleotides; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000633:toxicity
D015850:Interleukin-6; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha