TY - JOUR
T1 - Apoptosis inducing factor (AIF) mediates lethal redox stress induced by menadione
AU - Wiraswati, Hesti Lina
AU - Hangen, Emilie
AU - Sanz, Ana Belén
AU - Lam, Ngoc Vy
AU - Reinhardt, Camille
AU - Sauvat, Allan
AU - Mogha, Ariane
AU - Ortiz, Alberto
AU - Kroemer, Guido
AU - Modjtahedi, Nazanine
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Autophagy
KW - Mitochondria
KW - Oxidative stress
KW - Protein arylation
KW - Quinone metabolization
UR - http://www.scopus.com/inward/record.url?scp=84998886208&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.12562
DO - 10.18632/oncotarget.12562
M3 - Article
C2 - 27738311
AN - SCOPUS:84998886208
SN - 1949-2553
VL - 7
SP - 76496
EP - 76507
JO - Oncotarget
JF - Oncotarget
IS - 47
ER -