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BCL-xL overexpression effectively protects against tetrafluoroethylcysteine-induced intramitochondrial damage and cell death
- Source :
-
Biochemical Pharmacology . Jan2005, Vol. 69 Issue 1, p147-157. 11p. - Publication Year :
- 2005
-
Abstract
- 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, α-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 (21kDa) to the mitochondrial fraction after exposure to a cytotoxic concentration of TFEC (250μM). 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 (≤600μM), 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. [Copyright &y& Elsevier]
- Subjects :
- *GENE expression
*NEPHROTOXICOLOGY
*CELL death
*CYTOSOL
Subjects
Details
- Language :
- English
- ISSN :
- 00062952
- Volume :
- 69
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Biochemical Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 17122487
- Full Text :
- https://doi.org/10.1016/j.bcp.2004.08.030