Pesticide interactions induce alterations in secondary structure of malate dehydrogenase to cause destability and cytotoxicity

Environmental exposure to pesticides increases the risk of neurotoxicity and neurodegenerative diseases. The mechanism of pesticide-induced toxicity is attributed to the increased reactive oxygen species, mitochondrial dysfunction, inhibition of key cellular enzymes and accelerated pathogenic protein aggregation. The structural basis of pesticide-protein interaction is limited to pathogenic proteins such as α-synuclein, Tau and amyloid-beta. However, the effect of pesticides on metabolic proteins is still unexplored. Here, we used rotenone and chlorpyrifos to understand the interaction of these pesticides with a metabolic protein, malate dehydrogenase (MDH) and the consequent pesticide-induced cytotoxicity. We found that rotenone and chlorpyrifos strongly bind to MDH, interferes with protein folding and triggers alteration in its secondary structure. Both pesticides showed high binding affinities for MDH as observed by NMR and LCMS. Rotenone and chlorpyrifos induced structural alterations during MDH refolding resulting in the formation of cytotoxic conformers that generated oxidative stress and reduced cell viability. Our findings suggest that pesticides, in general, interact with proteins resulting in the formation of cytotoxic conformers that may have implications in neurotoxicity and neurodegenerative diseases. Pesticide induced cellular toxicity. (A) by inducing oxidative stress-mediated cellular signaling for apoptosis (B) enhancing the probability of pathogenic protein aggregation, seeding and cytotoxicity and (C) by interaction with non-pathogenic cellular proteins leading to their conformational alterations and cytotoxicity, where A and B pathways were known and reported earlier. [Display omitted] •Rotenone and chlorpyrifos bind to malate dehydrogenase with high binding affinity.•Pesticides interfere with MDH folding, triggers the structural alteration.•Structural alterations generate cytotoxic MDH conformers.•The pesticide induced MDH conformers may aggravate pesticide toxicity.