Open AccessIron handling in hippocampal neurons: activity‐dependent iron entry and mitochondria‐mediated neurotoxicity
Author(s) -
Pelizzoni Ilaria,
Macco Romina,
Morini Marco Francesco,
Zacchetti Daniele,
Grohovaz Fabio,
Codazzi Franca
Publication year - 2011
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/j.1474-9726.2010.00652.x
Subject(s) - neurotoxicity , mitochondrion , intracellular , reactive oxygen species , biology , microbiology and biotechnology , extracellular , hippocampal formation , oxidative stress , calcium in biology , transferrin receptor , cytosol , receptor , biochemistry , neuroscience , medicine , toxicity , enzyme
Summary The characterization of iron handling in neurons is still lacking, with contradictory and incomplete results. In particular, the relevance of non‐transferrin‐bound iron (NTBI), under physiologic conditions, during aging and in neurodegenerative disorders, is undetermined. This study investigates the mechanisms underlying NTBI entry into primary hippocampal neurons and evaluates the consequence of iron elevation on neuronal viability. Fluorescence‐based single cell analysis revealed that an increase in extracellular free Fe 2+ (the main component of NTBI pool) is sufficient to promote Fe 2+ entry and that activation of either N‐methyl‐ d ‐aspartate receptors (NMDARs) or voltage operated calcium channels (VOCCs) significantly potentiates this pathway, independently of changes in intracellular Ca 2+ concentration ([Ca 2+ ] i ). The enhancement of Fe 2+ influx was accompanied by a corresponding elevation of reactive oxygen species (ROS) production and higher susceptibility of neurons to death. Interestingly, iron vulnerability increased in aged cultures. Scavenging of mitochondrial ROS was the most powerful protective treatment against iron overload, being able to preserve the mitochondrial membrane potential and to safeguard the morphologic integrity of these organelles. Overall, we demonstrate for the first time that Fe 2+ and Ca 2+ compete for common routes (i.e. NMDARs and different types of VOCCs) to enter primary neurons. These iron entry pathways are not controlled by the intracellular iron level and can be harmful for neurons during aging and in conditions of elevated NTBI levels. Finally, our data draw the attention to mitochondria as a potential target for the treatment of the neurodegenerative processes induced by iron dysmetabolism.