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Regulation of tumor necrosis factor-induced, mitochondria- and reactive oxygen species-dependent cell death by the electron flux through the electron transport chain complex I.

Abstract：

:Tumor necrosis factor (TNF) induces a caspase-independent but mitochondria-dependent cell death process in the mouse fibrosarcoma cell line L929. Mitochondria actively participate in this TNF-induced necrotic cell death by the generation of mitochondrial reactive oxygen species (ROS). The aim of this study was to identify the mitochondrial components involved in TNF-induced production of ROS and their regulation by bioenergetic pathways. Therefore, we analyzed the bioenergetic characteristics in two metabolic L929 variants that exhibit different sensitivities to TNF. L929gln cells use glutamine as respiratory substrate and are far more susceptible to TNF-induced ROS generation and cell death as L929glc cells that use glucose as respiratory substrate. We show that the higher levels of reducing NAD(P)H equivalents, detected in the desensitized L929glc cells, do not cause diminished ROS generation. To the contrary, TNF increases the levels of NAD(P)H, probably altering complex I activity. A multiparameter analysis of electron flux through the mitochondrial electron transport chain, TNF-induced ROS levels, and cell death convincingly demonstrates a dependence of TNF signaling on complex I activity. Also, the sensitizing effect of glutamine metabolism correlates with an enhanced contribution of complex I to the overall electron flux. This participation of complex I activity in TNF-induced cell death is regulated by substrate availability rather than by a direct modification of complex I proteins. From the results presented in this paper we conclude that TNF-induced ROS generation and cell death are strongly regulated by bioenergetic pathways that define electron flux through complex I of the electron transport chain.

journal_name

Antioxid Redox Signal

journal_title

Antioxidants & redox signaling

authors

Goossens V,Stangé G,Moens K,Pipeleers D,Grooten J

doi

10.1089/ars.1999.1.3-285

keywords:

subject

Has Abstract

pub_date

1999-10-01 00:00:00

pages

285-95

issue

eissn

1523-0864

issn

1557-7716

journal_volume

pub_type

杂志文章

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Regulation of tumor necrosis factor-induced, mitochondria- and reactive oxygen species-dependent cell death by the electron flux through the electron transport chain complex I.