Energy/redox Metabolism Alterations in Response to Mitochondrial and Environmental Toxins: A Specific Role for Glucose-6-Phosphate-Dehydrogenase and the Pentose Phosphate Pathway in Paraquat Toxicity

摘要

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Neurotoxins MPP~+, rotenone, paraquat and 6-hydroxydopamine (6-OHDA) are typically used as toxicological models of PD. However, to date, there is no experimental model that recapitulates all the biochemical, pathological or symptomatic aspects of PD. Correspondingly, these neurotoxins have been report to induce their toxic effects via distinct mechanisms. However, these molecular mechanisms remain unclear. While energy failure and oxidative stress are involved in dopaminergic cell death in PD, very little is known regarding the alterations in energy metabolism associated with mitochondrial dysfunction and their causative role in cell death progression. The metabolome is a valuable source of information to understand disease pathogenesis since metabolites are more proximal to disease than genetic or proteomic information. In this study, we investigated the alterations in the energy/redox metabolome in dopaminergic cells exposed to environmental/mitochondrial toxins (paraquat, rotenone, MPP+ and 6-OHDA) in order to identify common and/or different mechanisms of toxicity.