Abstract

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. Ryanodine receptor-mediated Ca2+ release underlies iron-induced mitochondrial fission and stimulates mitochondrial Ca2+ uptake in primary hippocampal neurons (PDF Download Available). Available from: https://www.researchgate.net/publication/260999961_Ryanodine_receptor-mediated_Ca2_release_underlies_iron-induced_mitochondrial_fission_and_stimulates_mitochondrial_Ca2_uptake_in_primary_hippocampal_neurons [accessed Nov 24 2017].