Ryanodine Receptor-Mediated Ca(2+) Release Underlies Iron-Induced Mitochondrial Fission and Stimulates Mitochondrial Ca(2+) Uptake in Primary Hippocampal Neurons
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.
Más información
Título de la Revista: | FRONTIERS IN MOLECULAR NEUROSCIENCE |
Volumen: | 7 |
Número: | 13 |
Editorial: | FRONTIERS MEDIA SA |
Fecha de publicación: | 2014 |
Página de inicio: | 7 |
Página final: | 13 |
URL: | https://www.frontiersin.org/articles/10.3389/fnmol.2014.00013/full |
Notas: | WOS |