Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death.
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.
Seiler
Alexander
A
Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Marchioninistrasse 25, 81377 Munich, Germany.
Schneider
Manuela
M
Förster
Heidi
H
Roth
Stephan
S
Wirth
Eva K
EK
Culmsee
Carsten
C
Plesnila
Nikolaus
N
Kremmer
Elisabeth
E
Rådmark
Olof
O
Wurst
Wolfgang
W
Bornkamm
Georg W
GW
Schweizer
Ulrich
U
Conrad
Marcus
M