Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death

Alexander Seiler; Manuela Schneider; Heidi Förster; Stephan Roth; Eva K Wirth; Carsten Culmsee; Nikolaus Plesnila; Elisabeth Kremmer; Olof Rådmark; Wolfgang Wurst; Georg W Bornkamm; Ulrich Schweizer; Marcus Conrad

doi:10.1016/j.cmet.2008.07.005

Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death

Cell Metab. 2008 Sep;8(3):237-48. doi: 10.1016/j.cmet.2008.07.005.

Authors

Alexander Seiler¹, Manuela Schneider, Heidi Förster, Stephan Roth, Eva K Wirth, Carsten Culmsee, Nikolaus Plesnila, Elisabeth Kremmer, Olof Rådmark, Wolfgang Wurst, Georg W Bornkamm, Ulrich Schweizer, Marcus Conrad

Affiliation

¹ Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Marchioninistrasse 25, 81377 Munich, Germany.

PMID: 18762024
DOI: 10.1016/j.cmet.2008.07.005

Abstract

Oxidative stress in conjunction with glutathione depletion has been linked with various acute and chronic degenerative disorders, yet the molecular mechanisms have remained unclear. In contrast to the belief that oxygen radicals are detrimental to cells and tissues by unspecific oxidation of essential biomolecules, we now demonstrate that oxidative stress is sensed and transduced by glutathione peroxidase 4 (GPx4) into a-yet-unrecognized cell-death pathway. Inducible GPx4 inactivation in mice and cells revealed 12/15-lipoxygenase-derived lipid peroxidation as specific downstream event, triggering apoptosis-inducing factor (AIF)-mediated cell death. Cell death could be entirely prevented either by alpha-tocopherol (alpha-Toc), 12/15-lipoxygenase inhibitors, or siRNA-mediated AIF silencing. Accordingly, 12/15-lipoxygenase-deficient cells were highly resistant to glutathione depletion. Neuron-specific GPx4 depletion caused neurodegeneration in vivo and ex vivo, highlighting the importance of this pathway in neuronal cells. Since oxidative stress is common in the etiology of many human disorders, the identified pathway reveals promising targets for future therapies.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Animals
Apoptosis Inducing Factor / antagonists & inhibitors
Apoptosis Inducing Factor / metabolism*
Arachidonate 12-Lipoxygenase / deficiency
Arachidonate 12-Lipoxygenase / metabolism*
Arachidonate 15-Lipoxygenase / deficiency
Arachidonate 15-Lipoxygenase / metabolism*
Cell Death / drug effects
Cell Death / physiology
Cells, Cultured
Fluorenes / pharmacology
Genotype
Glutathione Peroxidase / deficiency
Glutathione Peroxidase / genetics
Glutathione Peroxidase / metabolism*
Hippocampus / metabolism
Hippocampus / pathology
Humans
Lipid Peroxidation / physiology
Mice
Mice, Congenic
Mice, Inbred C57BL
Mice, Knockout
Neurons / metabolism
Neurons / pathology
Oxidative Stress / physiology*
Phospholipid Hydroperoxide Glutathione Peroxidase
RNA, Small Interfering / pharmacology
Reverse Transcriptase Polymerase Chain Reaction
alpha-Tocopherol / pharmacology

Substances

6,11-dihydro-5-thia-11-aza-benzo(a)-fluorene
Apoptosis Inducing Factor
Fluorenes
RNA, Small Interfering
Phospholipid Hydroperoxide Glutathione Peroxidase
Glutathione Peroxidase
Arachidonate 12-Lipoxygenase
Arachidonate 15-Lipoxygenase
alpha-Tocopherol