The intrinsic apoptotic pathway lies upstream of reactive species production in cortical neurons and age-related oxidative stress in the brain

Abstract

A BAX- and mitochondria-dependent production of reactive oxygen species (ROS) and reactive species (reactive nitrogen species, RNS) lying downstream of these ROS occurs in apoptotic and nonapoptotic mouse sympathetic neurons and cerebellar granule cells in cell culture. These ROS have been shown to lie downstream of caspase 3 in mouse sympathetic neurons. Here we show that BAX is necessary for similar ROS production in apoptotic and nonapoptotic mouse cortical neurons in cell culture and that it also positively regulates oxidative stress in the brains of mice of different ages. Brains from mice with genetically reduced levels of mitochondrial superoxide dismutase 2 (SOD2) exhibited elevated levels of DNA strand breaks consistent with oxidative damage. Lipid peroxides were also elevated at some ages in comparison to the brains of wild type animals. BAX deletion in these mice reduced both brain DNA strand breaks and lipid peroxide levels to well below those of wild type animals. Deletion of caspase 3 greatly reduced age-augmented levels of brain oxidative stress markers including lipid peroxides, oxidized DNA, and nitrosylated proteins. These findings indicate that BAX contributes to ROS production in mouse cortical neurons, to oxidative stress their brains, and that this effect is likely mediated via caspase 3 activity.