<p>Among heavy metals, cadmium (Cd²⁺) is the most widespread pollutant, exhibiting pronounced neurotoxicity and exacerbating neurodegenerative diseases. Even at nanomolar concentrations in plasma, Cd²⁺ increases the risk of multiple disorders. The mechanisms underlying the detrimental effects of nanomolar Cd²⁺ on the nervous system are far from fully understood. Using microelectrode recordings and fluorescence approaches, we investigated the effects of low Cd²⁺ concentrations on acetylcholine release and redox balance at the mouse neuromuscular junction. Similar to voltage-gated Ca²⁺ channel blockers, Cd²⁺ (≥ 100 nM) suppressed evoked neurotransmitter release, but at a concentration of 20 nM Cd²⁺ selectively desynchronized exocytotic events. The latter effect was completely prevented by general (N-acetyl-L-cysteine) and mitochondrial (mitoTEMPO) antioxidants, but not by a TRPV1 antagonist. Cd²⁺ (20 nM) markedly increased reactive oxygen species (ROS) production, which was accompanied by lipid peroxidation and was blocked by mitoTEMPO. An NADPH oxidase inhibitor, VAS 2870 had no effect on Cd²⁺-dependent elevation of ROS levels. Zn²⁺ at nanomolar concentration completely prevented both the Cd²⁺-induced desynchronization of neurotransmitter release and the associated increase in ROS production. At the same time, nanomolar Zn²⁺ itself did not affect either the timing of acetylcholine release or redox status. Thus, Cd²⁺ at a nanomolar concentration disturbs the synchrony of evoked exocytotic events at the mouse neuromuscular synapse by enhancing mitochondrial ROS production. Zn²⁺ might be considered as an effective modulator of the synaptotoxicity of low-level Cd²⁺ exposure.</p> Graphical Abstract <p></p>