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

Abstract

Environmentalexposure to paraquat (PQ), a widely used herbicide, has been associated with anincreased risk of neurodegenerative diseases such as Parkinson’s disease.However, species-specific limitations of traditional animal models hindermechanistic insights into human neurotoxicity. We used a human-relevantcellular platform based on neural stem cells (NSCs) and neurons derived fromhuman induced pluripotent stem cells (hiPSCs) to investigate the differentialmitochondrial response and cell fate following PQ exposure. Our results revealthat hiPSC-derived neurons exhibit markedly higher susceptibility to PQ-inducedtoxicity than their corresponding neural progenitor cells. The neuronalvulnerability is characterized by profound mitochondrial membranedepolarization, reduced mitochondrial mass, elevated reactive oxygen species, increased nitric oxide levels, decreased ATPproduction, and activation of mitochondrial-dependent apoptosis pathways,including caspase-9 and caspase-3 cleavage, concomitant with an increasedBAX/BCL-XL ratio. In contrast, hiPSC-derivedNSCs maintain viability by upregulatingglycolytic activity, evidenced by increased GLUT-1 expression and hexokinaseactivity, suggesting a metabolic adaptation that supports resistance tomitochondrial impairment. Notably, the antioxidant N-acetyl-L-cysteinepartially restored mitochondrial membrane potential and metabolism in hiPSC-derived NSCs, but failed to protect neurons,highlighting cell-type-specific sensitivity. Alterations in mitochondrialdynamics, particularly decreased OPA-1 and MFN-2protein expression in neurons, further support a disruption in mitochondrialstructure and homeostasis. Our research highlights the translational potentialof hiPSC-derived neural models as a powerful platform for unravelling themechanisms of neurotoxicity induced by PQ and other chemicals associated withParkinson’s disease risk, aswell as for uncovering unique cellular responses to oxidative mitochondrialstress. These findings offer critical insights into neuronal vulnerabilityduring early development and provide a foundation for targeted interventions topreserve mitochondrial integrity in neurodegenerative contexts.