Abstract
Mitochondrial apoptosis inducing factor (AIF) is a redox-active enzyme that participates to the biogenesis/maintenance of complex I of the respiratory chain, yet also contributes to catabolic reactions in the context of regulated cell death when AIF translocates to the cytosol and to the nucleus. Here we explore the contribution of AIF to cell death induced by menadione (2-methyl-1,4-naphtoquinone; also called vitamin K3) in conditions in which this pro-oxidant does not cause the mitochondrial release of AIF, yet causes caspase-independent cell killing. Depletion of AIF from human cancer cells reduced the cytotoxicity of menadione. This cytoprotective effect was accompanied by the maintenance of high levels of reduced glutathione (GSH), which are normally depleted by menadione. In addition, AIF depletion reduced the arylation of cellular proteins induced by menadione. This menadione-triggered arylation, which can be measured by a fluorescence assay, is completely suppressed by addition of exogenous glutathione or N-acetyl cysteine. Complex I inhibition by Rotenone did not mimic the cytoprotective action of AIF depletion. Altogether, these results are compatible with the hypothesis that mitochondrion-sessile AIF facilitates lethal redox cycling of menadione, thereby precipitating protein arylation and glutathione depletion.
Highlights
Occurring quinone derivatives represent a wide range of compounds that are implicated in the regulation of crucial cellular processes such as mitochondrial respiration but have been successfully used as cytotoxic agents for anticancer therapy [1,2,3,4]
apoptosis inducing factor (AIF) is a redox active enzyme, and NADH oxidase [30] that has first been suggested to participate in antioxidant reactions as a reactive oxygen species (ROS) scavenger, meaning that its absence may sensitize cells to oxidant-induced stress [31]
In contrast with this interpretation, AIF potentiates cell death by pro-oxidants [22] including menadione (2-methyl-1,4-naphtoquinone) that has been explored for its therapeutic potential under the name of vitamin K3 [6]
Summary
Occurring quinone derivatives represent a wide range of compounds that are implicated in the regulation of crucial cellular processes such as mitochondrial respiration but have been successfully used as cytotoxic agents (e.g. daunorubicin, doxorubicin, geldanamycin and mitomycin C) for anticancer therapy [1,2,3,4]. Quinones, including those that are known for their anti-cancer properties, are classified as bioreductive compounds as their activity depends on their one- or two-electron reduction catalyzed by various cellular quinone reductases [5]. Two-electron reduction of menadione is responsible for the formation of a stable hydroquinone compound, without the generation of semiquinone as free radical intermediates, perhaps as an attempt to detoxify menadione [6, 7]
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