AUTHOR=SanMartín Carol D., Paula-Lima Andrea C., García Alejandra , Barattini Pablo , Hartel Steffen , Núñez Marco T., Hidalgo Cecilia TITLE=Ryanodine receptor-mediated Ca2+ release underlies iron-induced mitochondrial fission and stimulates mitochondrial Ca2+ uptake in primary hippocampal neurons JOURNAL=Frontiers in Molecular Neuroscience VOLUME=7 YEAR=2014 URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2014.00013 DOI=10.3389/fnmol.2014.00013 ISSN=1662-5099 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 Ca²⁺ signals and promotes cytoplasmic generation of reactive oxygen species. These Ca²⁺ signals, which emerge within seconds after iron addition, arise mostly from Ca²⁺ 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 Ca²⁺ release, generating long-lasting Ca²⁺ signals that activate Ca²⁺-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 Ca²⁺ 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 Ca²⁺ release by a RyR agonist promoted mitochondrial Ca²⁺ 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 Ca²⁺ increase induced by the Ca²⁺ ionophore ionomycin prompted significant mitochondrial Ca²⁺ uptake in neurons with fragmented mitochondria, indicating that fragmentation did not prevent mitochondrial Ca²⁺ uptake but presumably decreased the functional coupling between RyR-mediated Ca²⁺ release and the mitochondrial Ca²⁺ uniporter. Taken together, our results indicate that stimulation of redox-sensitive RyR-mediated Ca²⁺ release by iron causes significant neuronal mitochondrial fragmentation, which presumably contributes to the impairment of neuronal function produced by iron accumulation.