The study shows that chronic low-dose co-exposure to cadmium and paraquat drives mito-ROS–dependent OPA1 dysregulation, mitochondrial fragmentation, caspase-3–mediated GSDME cleavage, and dopaminergic neuron loss producing PD-like motor and cognitive deficits in mice.

By linking mitochondrial ROS and OPA1-dependent dynamics to caspase-3/GSDME-driven neuronal apoptosis with in vivo dopaminergic loss, the work identifies actionable targets (mito-ROS, OPA1, caspase-3/GSDME) and an environmental etiologic axis that can inform antioxidant, mitochondrial-dynamics, or…

The increasing environmental presence of cadmium (Cd) and paraquat (PQ), driven by industrial emissions and overuse of herbicide, poses heightened risks for neurodegenerative disorders. Although each of these toxins can independently induce neuronal damage, the synergistic neurotoxic effects resulting from chronic, low-dose co-exposure to Cd and PQ remain inadequately understood. This study demonstrates that exposure to subtoxic levels of Cd and PQ concurrently induces neuronal cell death and contributes to Parkinson's disease (PD)-like symptoms. Mechanistically, chronic co-exposure to Cd and PQ triggers a marked overproduction of mitochondrial ROS (mito-ROS), which impairs OPA1 processing and results in mitochondrial fragmentation. This mitochondrial dysfunction subsequently triggers caspase-3 activation, leading to GSDME cleavage and its translocation to the mitochondria, ultimately promoting neuronal apoptosis. Furthermore, our in vivo studies demonstrate significant mitochondrial dysfunction and loss of nigrostriatal dopaminergic neurons, resulting in motor deficits and cognitive impairments in mice co-exposed to these toxins. Collectively, our findings reveal a novel molecular mechanism involving the mito-ROS/OPA1/caspase-3/GSDME pathway in environmentally-induced PD-like pathology, thereby offering potential therapeutic insights for PD treatment.