Articulo
Ryanodine receptor-mediated ca2+ release underlies iron-induced mitochondrial fission and stimulates nnitochondrial ca2+ uptake in primary hippocampal neurons
FRONTIERS IN MOLECULAR NEUROSCIENCE;
Front. Molec. Neurosci.
Registro en:
0
D11I1096
D11I1096
WOS:000347962300001
1662-5099
Autor
San Martin, Carol D.
Paula-Lima, Andrea C.
Garcia-Acevedo, Alejandra
Barattini, Pablo
Hartel-Grundler, Steffen
Nunez, Marcos T.
Hidalgo, Cecilia
Institución
Resumen
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-beta 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. Financial Support: FONDECYT (11110322; 1100052; 1100599; 1130068; 1120579), ConicyT (79090021), FONDECYT-FONDAP (1501006), FONDEF D1111096, MILLENNIUM BNI (P-09015F), and PIA-CONICYT ACT1114. 2 FONDEF chidalgo@med.uchile.cl FONDECYT [11110322, 1100052, 1100599, 1130068, 1120579]; ConicyT [79090021]; FONDECYT-FONDAP [1501006]; FONDEF [D1111096]; MILLENNIUM BNI [P-09015F]; PIA-CONICYT [ACT1114] FONDEF