Excessive mitochondrial stress response triggers neuronal injury through the persistent eIF2α phosphorylation in mice exposed to manganese.

Manganese (Mn) overexposure-induced neurocognitive abnormalities are intensively linked to hippocampal neuronal injury, but the neurotoxic mechanisms involved are ambiguous. Under various mitochondrial stress, mitochondrial stress response (MSR) is activated and plays a dual role in cells, promoting adaptive survival while also contributing to detrimental damage, depending on the severity of mitochondrial dysfunction. Excessive MSR can lead to inevitable cell death and organ damage, ultimately driving the onset and progression of numerous disorders. Yet, whether excessive MSR is implicated in Mn-induced neuronal injury remains unclear. In this study, Mn poisoning models were established in C57BL/6 mice and hippocampal primary neurons to investigate the role of excessive MSR in mitochondria-mediated neuronal apoptosis following Mn exposure. Specifically, excessive MSR triggered hippocampal neuronal mitochondrial damage and neurocognitive abnormalities, which was primarily driven by the persistent phosphorylation of eukaryotic translation initiation factor 2α (eIF2α). Furthermore, excessive acetylation of growth arrest and DNA damage-inducible protein 34 (GADD34) impaired the dephosphorylation of phospho-eIF2α by disrupting the protein phosphatase 1α/GADD34 complex in primary neurons following Mn exposure. Finally, Sirtuin 1-mediated GADD34 deacetylation facilitated the dephosphorylation of phospho-eIF2α, thus mitigating excessive MSR-triggered neuronal apoptosis and mitochondrial dysfunction. These findings underscore the critical role and complexity of excessive MSR in Mn-induced neuronal injury.