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Apoptosis inducing factor (AIF) mediates lethal redox stress induced by menadione

Hesti Lina Wiraswati1,2,3,4,5, Emilie Hangen1,2,3,4, Ana Belén Sanz1,2,3,4,6

  • 1Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.

Oncotarget
|October 15, 2016
PubMed

Insights

Mitochondrial apoptosis-inducing factor (AIF) depletion protects cancer cells from menadione-induced death by preserving glutathione levels and reducing protein arylation. This suggests AIF facilitates menadione

Area of Science:

  • Cellular Biology
  • Biochemistry
  • Oxidative Stress Research

Background:

  • Mitochondrial apoptosis-inducing factor (AIF) is involved in cell death pathways and mitochondrial complex I function.
  • Menadione (vitamin K3) is a pro-oxidant that can induce cell death.
  • The role of AIF in menadione-induced, caspase-independent cell death is not fully understood.

Purpose of the Study:

  • To investigate the role of AIF in menadione-induced cytotoxicity in human cancer cells.
  • To elucidate the mechanisms by which AIF contributes to menadione toxicity.

Main Methods:

  • Depletion of AIF in human cancer cells.
  • Assessment of menadione cytotoxicity.
  • Measurement of reduced glutathione (GSH) levels.
  • Quantification of menadione-induced protein arylation using a fluorescence assay.
  • Inhibition of mitochondrial Complex I with Rotenone.

Main Results:

  • AIF depletion significantly reduced menadione-induced cancer cell death.
  • AIF-depleted cells maintained higher levels of reduced glutathione (GSH) after menadione treatment.
  • Depletion of AIF decreased menadione-induced protein arylation.
  • Rotenone inhibition of Complex I did not replicate the cytoprotective effect of AIF depletion.

Conclusions:

  • Mitochondrion-resident AIF plays a crucial role in facilitating menadione-induced cell death.
  • AIF promotes menadione toxicity by enabling lethal redox cycling, leading to GSH depletion and protein arylation.
  • Targeting AIF may offer a strategy to sensitize cancer cells to pro-oxidant therapies.
Keywords:
Autophagymitochondriaoxidative stressprotein arylationquinone metabolization

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