Iron handling in hippocampal neurons: Activity-dependent iron entry and mitochondria-mediated neurotoxicity

Ilaria Pelizzoni, Romina Macco, Marco Francesco Morini, Daniele Zacchetti, Fabio Grohovaz, Franca Codazzi

Research output: Contribution to journalArticlepeer-review


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 Fe2+ (the main component of NTBI pool) is sufficient to promote Fe2+ 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 Ca2+ concentration ([Ca2+]i). The enhancement of Fe2+ 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 Fe2+ and Ca2+ 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.

Original languageEnglish
Pages (from-to)172-183
Number of pages12
JournalAging Cell
Issue number1
Publication statusPublished - Feb 2011


  • Calcium
  • Hippocampal neurons
  • Iron
  • Mitochondria
  • Neurotoxicity
  • Oxidative stress

ASJC Scopus subject areas

  • Cell Biology
  • Ageing


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