Inhibition of mitochondrial complex III causes selective dopaminergic neurotoxicity by redox stress in Caenorhabditis...

Environmental factors including chemical exposures are important contributors to Parkinson's disease (PD). Nearly all well-validated chemicals involved in PD affect mitochondria, and the great majority of those identified inhibit mitochondrial complex I, causing ATP depletion and oxidative stress. We hypothesized that inhibition of mitochondrial complex III would also cause dopaminergic neurotoxicity. Using Caenorhabditis elegans to evaluate the in vivo effects of complex III-inhibiting pesticides antimycin A and pyraclostrobin, we found that both caused selective dopaminergic neurotoxicity. We evaluated exacerbation of dopaminergic neurotoxicity by the presence of α-synuclein, and pdr-1/PRKN and pink-1/PINK1 mutant backgrounds and found increased neurotoxicity for pdr-1. Complex III inhibition caused a more-oxidized cellular environment in those neurons and pharmacological and genetic antioxidant interventions rescued neurotoxicity, but energetic rescue attempts did not. Finally, optogenetic production of superoxide anion specifically at complex III caused dopaminergic neuronal damage. Thus, redox stress at complex III following chemical exposure causes dopaminergic neurotoxicity in vivo in C. elegans.