"Susceptibility of hiPSC-derived NSCs and neurons to paraquat treatment: insights into differential neurotoxicity mechanisms related to mitochondria."

Abstract

Environmental exposure to paraquat (PQ), a widely used herbicide, has been associated with an increased risk of neurodegenerative diseases such as Parkinson's disease. However, species-specific limitations of traditional animal models hinder mechanistic insights into human neurotoxicity. We used a human-relevant cellular platform based on neural stem cells (NSCs) and neurons derived from human induced pluripotent stem cells (hiPSCs) to investigate the differential mitochondrial response and cell fate following PQ exposure. Our results reveal that hiPSC-derived neurons exhibit markedly higher susceptibility to PQ-induced toxicity than their corresponding neural progenitor cells. The neuronal vulnerability is characterized by profound mitochondrial membrane depolarization, reduced mitochondrial mass, elevated reactive oxygen species, increased nitric oxide levels, decreased ATP production, and activation of mitochondrial-dependent apoptosis pathways, including caspase-9 and caspase-3 cleavage, concomitant with an increased BAX/BCL-XL ratio. In contrast, hiPSC-derived NSCs maintain viability by upregulating glycolytic activity, evidenced by increased GLUT-1 expression and hexokinase activity, suggesting a metabolic adaptation that supports resistance to mitochondrial impairment. Notably, the antioxidant N-acetyl-L-cysteine partially restored mitochondrial membrane potential and metabolism in hiPSC-derived NSCs, but failed to protect neurons, highlighting cell-type-specific sensitivity. Alterations in mitochondrial dynamics, particularly decreased OPA-1 and MFN-2 protein expression in neurons, further support a disruption in mitochondrial structure and homeostasis. Our research highlights the translational potential of hiPSC-derived neural models as a powerful platform for unravelling the mechanisms of neurotoxicity induced by PQ and other chemicals associated with Parkinson's disease risk, as well as for uncovering unique cellular responses to oxidative mitochondrial stress. These findings offer critical insights into neuronal vulnerability during early development and provide a foundation for targeted interventions to preserve mitochondrial integrity in neurodegenerative contexts.