Brain region specificity of 3-nitropropionic acid-induced vulnerability of neurons involves cytochrome c oxidase.

Mitochondria play a pivotal role in the regulation of energy metabolism and apoptotic pathways. Properties and functions of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to a different extent to cellular stress and degeneration. We have investigated the effect of 3-nitropropionic acid (NPA), a mitochondrial toxin and mimicking symptoms of Huntington's disease (HD) when applied systemically, on mitochondrial function and viability of primary neurons isolated from mouse brain striatum and cortex. We observed a higher vulnerability of striatal compared with cortical neurons in response to NPA treatment. This effect might be correlated with the transcription pattern of cytochrome c oxidase (EC 1.9.3.1.; COX) subunit IV isoforms. In cortical neurons, NPA induced a down-regulation of the COX IV-2/COX IV-1 ratio, whereas an up-regulation was found in striatal neurons. Previously, we have shown that an increased COX IV-2/COX IV-1 ratio is responsible for a higher enzyme activity which is paralleled by elevated intracellular ATP levels at the expense of increased mitochondrial peroxide production. These effects could also be demonstrated in striatal neurons. On the contrary, a decreased COX IV-2/COX IV-1 ratio was observed in cortical neurons which was accompanied by a decrease in intracellular ATP content and no significant changes in mitochondrial peroxide production. We propose that COX isoform IV-2 mediates increased oxidative stress that is, at least in part, responsible for a higher vulnerability of striatal compared with cortical neurons against NPA. This mechanism, in turn, may serve as an explanation for brain region-specific differences in the neuronal susceptibility to toxic conditions.