BCL-xL overexpression effectively protects against tetrafluoroethylcysteine-induced intramitochondrial damage and cell death.

Abstract

S-(1,1,2,2-Tetrafluoroethyl)-L-cysteine (TFEC), a major metabolite of the industrial gas tetrafluoroethylene, has been shown to mediate nephrotoxicity by necrosis. TFEC-induced cell death is associated with an early covalent modification of specific intramitochondrial proteins; including aconitase, alpha-ketoglutarate dehydrogenase (KGDH) subunits, HSP60 and HSP70. Previous studies have indicated that the TAMH line accurately models TFEC-induced in vivo cell death with dose- and time-dependent inhibitions of both KGDH and aconitase activities. Here, we show that the molecular pathway leading to TFEC-mediated cell death is associated with an early cytosolic to mitochondrial translocation of BAX, a pro-apoptotic member of the BCL-2 family. Immunoblot analyses indicated movement of BAX (21 kDa) to the mitochondrial fraction after exposure to a cytotoxic concentration of TFEC (250 microM). Subsequent cytochrome c release from mitochondria was also demonstrated, but only a modest increase in caspase activities was observed, suggesting a degeneration of early apoptotic signals into secondary necrosis. Significantly, TAMH cells overexpressing BCL-xL preserved cell viability even to supratoxicological concentrations of TFEC (< or =600 microM), and this cytoprotection was associated with decreased HSP70i upregulation, indicating suppression of TFEC-induced proteotoxicity. Hence, TFEC-induced necrotic cell death in the TAMH cell line is mediated by BAX and antagonized by the anti-apoptotic BCL-2 family member, BCL-xL.

• Authors: Han K Ho, Zhong-Hua Hu, Shie-Pon Tzung, David M Hockenbery, Nelson Fausto, Sidney D Nelson, Sam A Bruschi
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 69 Issue 1 Pg. 147-57 (Jan 01 2005) ISSN: 0006-2952 [Print] England
• PMID: 15588723 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• BCL2L1 protein, human
• Fluorocarbons
• Proto-Oncogene Proteins c-bcl-2
• bcl-X Protein
• Cysteine
• tetrafluoroethylene

Topics

• Cell Death (drug effects, genetics)
• Cell Line
• Cysteine (metabolism, pharmacology)
• Fluorocarbons (metabolism, pharmacology)
• Gene Expression Regulation (drug effects, physiology)
• Humans
• Mitochondria (drug effects, genetics)
• Proto-Oncogene Proteins c-bcl-2 (biosynthesis, physiology)
• bcl-X Protein