Apoptosis Inducing Factor (AIF) Mediates Lethal Redox Stress Induced by Menadione

Overview

Journal Oncotarget

Specialty Oncology

Date 2016 Oct 15

PMID 27738311

Citations 8

Authors

Hesti Lina Wiraswati

Emilie Hangen

Ana Belen Sanz

Ngoc-Vy Lam

Camille Reinhardt

Allan Sauvat

Ariane Mogha

Alberto Ortiz

Guido Kroemer

Nazanine Modjtahedi

Affiliations

Soon will be listed here.

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.

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