Lead induced intracellular copper redox imbalance with aggravated cellular dysfunction.

Lead (Pb) represents a critical environmental health concern due to its profound impact on neurodegenerative processes, yet its specific influences on copper (Cu) redox states and associated cellular dysfunction remain inadequately understood. Cu is an essential element required for numerous physiological processes, with its redox equilibrium being particularly critical for mitochondrial function. In this study, we used SH-SY5Y cells as normal human neuron cells and constructed Alzheimer Disease (AD) cell model to study the effects of Pb toxicity in AD-like pathogenesis in human neuron cells. To investigate the toxicity of Pb on Cu redox dynamics and cellular responses, the subcellular locations of Cu(II) and Cu(I) were imaged and combined with proteomic analysis in SH-SY5Y cells and AD cell model. Our findings revealed that Pb exposure promoted the oxidation of Cu(I) to Cu(II), resulting in aberrant Cu(II) accumulation in mitochondria and lysosomes, ultimately disrupting intracellular Cu homeostasis. This imbalance was associated with mitochondrial dysfunction, increased oxidative stress, and impaired cellular integrity. Proteomic analyses further demonstrated that Pb exposure dysregulated proteins involved in cellular metal ion homeostasis especially for Cu ion, up-regulated the AD pathologies proteins (e.g. APP), underscoring the central role of mitochondrial damage in Pb-induced cytotoxicity in AD. Collectively, these results revealed a plausible mechanism by which Pb induced intracellular Cu redox imbalance by reducing Cu(I) to Cu(II) and aggravated AD pathogenesis. Our study provides critical insights into the molecular basis of Pb cytotoxicity and aggravation of AD pathogenesis in normal neuron and AD cell model with environmental Pb exposure.