Pesticides and impairment of mitochondrial function in relation with the parkinsonian syndrome

Abstract

The Parkinsonian syndrome induced by pesticides is associated with the impairment of mitochondrial function. Toxicants that inhibit selectively NADH-dehydrogenase activity, as rotenone or pyridaben, also show a selective inhibition of O2 uptake and respiratory control in rat brain mitochondria in the presence of NAD-dependent substrates. The IC50 of rotenone and pyridaben for complex I inhibition were in the range 1.7-2.2 microM. The determination of NADH-cytochrome c reductase, succinate-cytochrome c reductase and cytochrome oxidase activities in rat brain submitochondrial showed again the selective inhibition of Complex I by rotenone and pyridaben, whereas paraquat produced a non-selective inhibition affecting all the respiratory chain complexes. In rat brain mitochondria, rotenone and pyridaben markedly decreased mtNOS functional activity with NAD-dependent substrates but not when the substrate was succinate. This observation suggest than mtNOS activity is regulated by the activity of complex I. This regulation and the role of mitochondrial NO diffusion as a signal for mitochondrial biogenesis could have a role in the etiopathology of Parkinson's disease.

Cytotoxicity of paraquat in microglial cells: Involvement of PKCδ- and ERK1/2-dependent NADPH oxidase

“…Mitochondrial dysfunction and mitochondrial-induced apoptosis have been demonstrated in paraquat toxicity in dopaminergic cells (Gomez et al, 2007;GonzalezPolo et al, 2004;McCarthy et al, 2004;Richardson et al, 2005). Our results show that paraquat-induced cytotoxicity is preceded by the increase in ROS production.…”

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…Complex I impairment seems to be important for the pathogenesis of PD since exposure to inhibitors of this complex, such as MPP + or rotenone, reproduces the clinical symptoms of PD observed in human subjects [105,106].Complex I is the largest of the electron transport chain (ETC) complexes, consisting of 46 subunits, 7 of which are encoded by mitochondrial DNA (mtDNA) [107]and the major site of superoxide production in the ETC [108]. Complex I activity and expression are decreased in the SN[109Ͳ112] and cortex [113] of PD patients to a greater extent than would be expected from normal aging [107].…”

Placental Toxicology of Pesticides

“…Because the mitochondria is a ROS source and is an organelle enriched with polyunsaturated fatty acids, the impairment of the mitochondrial function may increase ROS production and lipoperoxides. Some pesticides directly affect the mitochondrial electron transfer chain, which leads to a further increased formation of damaging ROS and nitrogen free radicals (Gomez et al, 2007). The effects of OP (parathion, dichlorvos) and OC (dieldrin and DDE) on the mitocondrial function have been studied in diverse experimental systems, and have identified ROS generation and the inhibition of the electron transport chain complexes, along with ATP-synthase and phosphate transporters, to be the primary mechanisms of action.…”