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Updated: Sep 12, 2025
Modeling Neuronal Death and Degeneration in Mouse Primary Cerebellar Granule Neurons
Published on: November 6, 2017
Excessive mitochondrial stress response triggers neuronal injury through the persistent eIF2α phosphorylation in mice
Yunfei Jia1, Bin He1, Keyu Chen1
1Program of Environmental Physical Factors and Health, School of Public Health, China Medical University, Shenyang, Liaoning 110122, China.
Abstract:
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.
Insights
Manganese (Mn) overexposure causes neurocognitive issues by damaging hippocampal neurons. Excessive mitochondrial stress response (MSR) drives this damage via persistent eIF2α phosphorylation, leading to neuronal apoptosis.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Manganese (Mn) overexposure is linked to neurocognitive deficits and hippocampal neuronal injury.
- Mitochondrial stress response (MSR) plays a dual role in cellular adaptation and damage.
- The role of excessive MSR in Mn-induced neuronal injury is not well understood.
Purpose of the Study:
- To investigate the role of excessive MSR in Mn-induced neuronal apoptosis.
- To elucidate the mechanisms underlying Mn neurotoxicity in the hippocampus.
Main Methods:
- Establishment of Mn poisoning models in C57BL/6 mice and primary hippocampal neurons.
- Analysis of mitochondrial damage, neurocognitive abnormalities, and apoptosis markers.
- Investigation of key protein modifications: eIF2α phosphorylation and GADD34 acetylation/deacetylation.
Main Results:
- Excessive MSR was found to trigger hippocampal neuronal mitochondrial damage and neurocognitive abnormalities in Mn-exposed mice.
- Persistent phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) was identified as a primary driver of Mn-induced neuronal injury.
- Excessive acetylation of growth arrest and DNA damage-inducible protein 34 (GADD34) disrupted the protein phosphatase 1α/GADD34 complex, impairing eIF2α dephosphorylation.
- Sirtuin 1-mediated GADD34 deacetylation mitigated excessive MSR, neuronal apoptosis, and mitochondrial dysfunction.
Conclusions:
- Excessive MSR plays a critical and complex role in Mn-induced neuronal injury.
- Persistent eIF2α phosphorylation and dysregulated GADD34 acetylation are key mechanisms in Mn neurotoxicity.
- Targeting Sirtuin 1-mediated pathways may offer therapeutic potential for Mn-induced neurocognitive disorders.
