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Mounting evidence indicates that iron accumulation impairs brain function. We have reported previously that addition of sub-lethal concentrations of iron to primary hippocampal neurons produces Ca 2  +  signals and promotes cytoplasmic generation of reactive oxygen species. These Ca 2  +  signals, which emerge within seconds after iron addition, arise mostly from Ca 2  +  release through the redox-sensitive ryanodine receptor (RyR) channels present in the endoplasmic reticulum. We have reported also that addition of synaptotoxic amyloid-β oligomers to primary hippocampal neurons stimulates RyR-mediated Ca 2  +  release, generating long-lasting Ca 2  +  signals that activate Ca 2  + -sensitive cellular effectors and promote the disruption of the mitochondrial network. Here, we describe that 24 h incubation of primary hippocampal neurons with iron enhanced agonist-induced RyR-mediated Ca 2  +  release and promoted mitochondrial network fragmentation in 43% of neurons, a response significantly prevented by RyR inhibition and by the antioxidant agent  N -acetyl- L -cysteine. Stimulation of RyR-mediated Ca 2  +  release by a RyR agonist promoted mitochondrial Ca 2  +  uptake in control neurons and in iron-treated neurons that displayed non-fragmented mitochondria, but not in neurons with fragmented mitochondria. Yet, the global cytoplasmic Ca 2  +  increase induced by the Ca 2  +  ionophore ionomycin prompted significant mitochondrial Ca 2  +  uptake in neurons with fragmented mitochondria, indicating that fragmentation did not prevent mitochondrial Ca 2  +  uptake but presumably decreased the functional coupling between RyR-mediated Ca 2  +  release and the mitochondrial Ca 2  +  uniporter. Taken together, our results indicate that stimulation of redox-sensitive RyR-mediated Ca 2  +  release by iron causes significant neuronal mitochondrial fragmentation, which presumably contributes to the impairment of neuronal function produced by iron accumulation.

frontiers in molecular neuroscience

Ryanodine receptor-mediated Ca2+ release underlies iron-induced mitochondrial fission and stimulates mitochondrial Ca2+ uptake in primary hippocampal neurons