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PMID: 8344250 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Depletion of the mitochondrial electron transport abrogates the cytotoxic and gene-inductive effects of TNF.

The EMBO journal ·Vol. 12 ·No. 8 ·1993-08-00 ·Pages 3095-104

Schulze-Osthoff K, Beyaert R, Vandevoorde V, Haegeman G, Fiers W

Abstract

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.

MeSH Terms
Animals Base Sequence Cell Survival/drug effects Cells, Cultured Electron Transport Gene Expression Regulation/drug effects Interleukin-6/genetics Mice Mitochondria/drug effects,metabolism Molecular Sequence Data NF-kappa B/biosynthesis,genetics Oligodeoxyribonucleotides Reactive Oxygen Species/metabolism Signal Transduction Transcriptional Activation Tumor Necrosis Factor-alpha/antagonists & inhibitors,pharmacology,toxicity
Chemicals
Interleukin-6 NF-kappa B Oligodeoxyribonucleotides Reactive Oxygen Species Tumor Necrosis Factor-alpha
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Schulze-Osthoff K
Laboratory of Molecular Biology, University of Ghent, Belgium.
Beyaert R
Vandevoorde V
Haegeman G
Fiers W
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
Published
1993-08-00
Pages
3095-104
Language
English
Region
England
NLM ID
8208664
PMCID
PMC413574
Subset
IM
External Links
PubMed source PMC Full Text View journal details
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