Bid-mediated mitochondrial damage is a key mechanism in glutamate-induced oxidative stress and AIF-dependent cell death in immortalized HT-22 hippocampal neurons

Carsten Culmsee (1) , Svenja Tobaben (1) , Julia Grohm (1) , Alexander Seiler (1) , Marcus Conrad (1) , Nikolaus Plesnila (1)

1 Pharmacy

Glutamate toxicity involves increases in intracellular calcium levels and enhanced formation of reactive oxygen species (ROS) causing neuronal dysfunction and death in acute and chronic neurodegenerative disorders. The molecular mechanisms mediating glutamate-induced ROS formation are, however, still poorly defined. Using a model system that lacks glutamate operated calcium channels we demonstrate that glutamate-induced acceleration of ROS levels occurs in two steps and is initiated by lipoxygenases (LOX) and then significantly accelerated through Bid-dependent mitochondrial damage. The Bid-mediated secondary boost of ROS formation downstream of LOX activity further involves mitochondrial fragmentation and release of mitochondrial AIF to the nucleus. These data imply that the activation of Bid is an essential step in amplifying glutamate-induced formation of lipid peroxides to irreversible mitochondrial damage associated with further enhanced free radical formation and AIF-dependent execution of cell death.

Mots clés: glutamate; neuronal cell death; apoptosis; mitochondria; lipid peroxidation

Carsten Culmsee, Svenja Tobaben, Julia Grohm, Alexander Seiler, Marcus Conrad, et al.. Bid-mediated mitochondrial damage is a key mechanism in glutamate-induced oxidative stress and AIF-dependent cell death in immortalized HT-22 hippocampal neurons. Cell Death and Differentiation, 2010, ⟨10.1038/cdd.2010.92⟩. ⟨hal-00563513⟩