In Vitro Studies of Ferritin Iron Release and Neurotoxicity

Abstract

The increase in brain iron associated with several neurodegenerative diseases may lead to an increased production of free radicals via the Fenton reaction. Intracellular iron is usually tightly regulated, being bound by ferritin in an insoluble ferrihydrite core. The neurotoxin 6‐hydroxydopamine (6‐OHDA) releases iron from the ferritin core by reducing it to the ferrous form. Iron release induced by 6‐OHDA and structurally related compounds and two other dopaminergic neurotoxins, 1‐methyl‐4‐phenylpyridinium iodide (MPP+) and 1‐trichloromethyl‐1,2,3,4‐tetrahydro‐β‐carboline (TaClo), were compared, to identify the structural characteristics important for such release. 1,2,4‐Trihydroxybenzene (THB) was most effective in releasing ferritin‐bound iron, followed by 6‐OHDA, dopamine, catechol, and hydroquinone. Resorcinol, MPP+, and TaClo were ineffective. The ability to release iron was associated with a low oxidation potential. It is proposed that a low oxidation potential and an ortho‐dihydroxyphenyl structure are important in the mechanism by which ferritin iron is mobilized. In the presence of ferritin, both 6‐OHDA and THB strongly stimulated lipid peroxidation, an effect abolished by the addition of the iron chelator deferoxamine. These results suggest that ferritin iron release contributes to free radical‐induced cell damage in vivo.

Interactions Between Environmental and Genetic Factors in the Pathophysiology of Parkinson's Disease

“…Results from several studies suggest that ferritin in the SNpc is not increased concomitantly with iron (26). Although it has been previously speculated that increasing iron loading by ferritin may increase the risk of free radical damage to the cell (27), a recent in vivo study has shown that genetically enhanced expression of ferritin and pharmacological iron chelation (clioquinol) prevents MPTP-induced neurotoxicity (28). This evidence substantiates the significance of iron homeostasis in preventing and postponing the progression of PD.…”

Protective effects of carnosine and homocarnosine on ferritin and hydrogen peroxide-mediated DNA damage

“…It has been reported that iron can be released from ferritin by various exogenous (2)(3)(4)(5) and endogenous substances via reductive mechanisms (6,7). If iron is released from ferritin, low molecular weight iron complexes may undergo redox reactions, resulting in cytotoxic damage to macromolecules (8,9).…”

Physiological origin of biogenic magnetic nanoparticles in health and disease: from bacteria to humans

“…In this context, the bioinformatic analysis in the paper 214 proves that the biomineralization of BMNPs is in general a process independent of iron storage in the core of ferritin and ferritinlike proteins. However, in our opinion, an excess of labile iron related to the decreased ability of ferritin to retain iron within its core in pathological conditions 123,169 may represent an additional iron supply for BMNP biomineralization. Besides, the biomineralization of BMNPs can protect tissues against oxidative stress, since iron in magnetite is bound irreversibly and cannot be released for the Fenton reaction.…”

“…22,122,123 A hypothesis has been proposed that the ferrihydrite core of ferritin can be a precursor of magnetite, by analogy to what is observed in MTB, which in an early growth stage produce …”