Inflammation and iron accumulation are present in a variety of neurodegenerative diseases that include Alzheimer's disease and Parkinson's disease. The study of the putative association between inflammation and iron accumulation in central nervous system cells is relevant to understand the contribution of these processes to the progression of neuronal death. In this study, we analyzed the effects of the inflammatory cytokines tumor necrosis factor alpha (TNF-a) and interleukin 6 (IL-6) and of lipopolysaccharide on total cell iron content and on the expression and abundance of the iron transporters divalent metal transporter 1 (DMT1) and Ferroportin 1 (FPN1) in neurons, astrocytes and microglia obtained from rat brain. Considering previous reports indicating that inflammatory stimuli induce the systemic synthesis of the master iron regulator hepcidin, we identified brain cells that produce hepcidin in response to inflammatory stimuli, as well as hepcidin-target cells. We found that inflammatory stimuli increased the expression of DMT1 in neurons, astrocytes, and microglia. Inflammatory stimuli also induced the expression of hepcidin in astrocytes and microglia, but not in neurons. Incubation with hepcidin decreased the expression of FPN1 in the three cell types. The net result of these changes was increased iron accumulation in neurons and microglia but not in astrocytes. The data presented here establish for the first time a causal association between inflammation and iron accumulation in brain cells, probably promoted by changes in DMT1 and FPN1 expression and mediated in part by hepcidin. This connection may potentially contribute to the progression of neurodegenerative diseases by enhancing iron-induced oxidative damage.

Iron is an essential element for life on earth, participating in a plethora of cellular processes where one-electron transfer reactions are required. Its essentiality, coupled to its scarcity in aqueous oxidative environments, has compelled living organisms to develop mechanisms that ensure an adequate iron supply, at times with disregard to long-term deleterious effects derived from iron accumulation. However, iron is an intrinsic producer of reactive oxygen species, and increased levels of iron promote neurotoxicity because of hydroxyl radical formation, which results in glutathione consumption, protein aggregation, lipid peroxidation and nucleic acid modification. Neurons from brain areas sensitive to degeneration accumulate iron with age and thus are subjected to an ever increasing oxidative stress with the accompanying cellular damage. The ability of these neurons to survive depends on the adaptive mechanisms developed to cope with the increasing oxidative load. Here, we describe the chemical and thermodynamic peculiarities of iron chemistry in living matter, review the components of iron homeostasis in neurons and elaborate on the mechanisms by which iron homeostasis is lost in Parkinson's disease, Alzheimer's disease and other diseases in which iron accumulation has been demonstrated.

Hallmarks of idiopathic and some forms of familial Parkinson’s disease are mitochondrial dysfunction, iron accumulation and oxidative stress in dopaminergic neurons of the substantia nigra. There seems to be a causal link between these three conditions, since mitochondrial dysfunction can give rise to increased electron leak and reactive oxygen species production. In turn, recent evidence indicates that diminished activity of mitochondrial complex I results in decreased Fe–S cluster synthesis and anomalous activation of Iron Regulatory Protein 1. Thus, mitochondrial dysfunction could be a founding event in the process that leads to neuronal death. Here, we present evidence showing that at low micromolar concentrations, the dopamine metabolite aminochrome inhibits complex I and ATP production in SH-SY5Y neuroblastoma cells differentiated into a dopaminergic phenotype. This effect is apparently direct, since it is replicated in isolated mitochondria. Additionally, overnight treatment with aminochrome increased the expression of the iron import transporter divalent metal transporter 1 and decreased the expression of the iron export transporter ferroportin 1. In accordance with these findings, cells treated with aminochrome presented increased iron uptake. These results suggest that aminochrome is an endogenous toxin that inhibits by oxidative modifications mitochondrial complex I and modifies the levels of iron transporters in a way that leads to iron accumulation.

Recent evidence suggests that reactive oxygen species function as second messenger molecules in normal physiological processes. For example, activation of N-Methyl-D-Aspartate receptor results in the production of ROS, which appears to be critical for synaptic plasticity, one of the cellular mechanisms that underlie learning and memory. In this work, we studied the effect of iron in the activation of MAPK/ERK pathway and on Ca 2+ signaling in neuronal PC12 cells. We found that iron-dependent generation of hydroxyl radicals is likely to modulate Ca 2+ signaling through RyR calcium channel activation, which, in turn, activates the MAPK/ERK pathway. These findings underline the relevance of iron in normal neuronal function.

Mitochondrial dysfunction, iron accumulation, and oxidative damage are conditions often found in damaged brain areas of Parkinson's disease. We propose that a causal link exists between these three events. Mitochondrial dysfunction results not only in increased reactive oxygen species production but also in decreased iron-sulfur cluster synthesis and unorthodox activation of Iron Regulatory Protein 1 (IRP1), a key regulator of cell iron homeostasis. In turn, IRP1 activation results in iron accumulation and hydroxyl radical-mediated damage. These three occurrences—mitochondrial dysfunction, iron accumulation, and oxidative damage—generate a positive feedback loop of increased iron accumulation and oxidative stress. Here, we review the evidence that points to a link between mitochondrial dysfunction and iron accumulation as early events in the development of sporadic and genetic cases of Parkinson's disease. Finally, an attempt is done to contextualize the possible relationship between mitochondria dysfunction and iron dyshomeostasis. Based on published evidence, we propose that iron chelation—by decreasing iron-associated oxidative damage and by inducing cell survival and cell-rescue pathways—is a viable therapy for retarding this cycle.