Neuronal iron homeostasis disruption and oxidative stress are closely related to the pathogenesis of Parkinson's disease (PD). Adult iron-regulatory protein 2 knockout (Ireb2(-/-)) mice develop iron accumulation in white matter tracts and nuclei in different brain area and display severe neurodegeneration in Purkinje cells of the cerebrum. Mitochondrial ferritin (MtFt), a newly discovered ferritin, specifically expresses in high energy-consuming cells, including neurons of brain and spinal cord. Interestingly, the decreased expression of MtFt in cerebrum, but not in striatum, matches the differential neurodegeneration pattern in these Ireb2(-/-) mice. To explore its effect on neurodegeneration, the effects of MtFt expression on 6-hydrodopamine (6-OHDA)-induced neuronal damage was examined. The overexpression of MtFt led to a cytosolic iron deficiency in the neuronal cells and significantly prevented the alteration of iron redistribution induced by 6-OHDA. Importantly, MtFt strongly inhibited mitochondrial damage, decreased production of the reactive oxygen species and lipid peroxidation, and dramatically rescued apoptosis by regulating Bcl-2, Bax and caspase-3 pathways. In conclusion, this study demonstrates that MtFt plays an important role in preventing neuronal damage in an 6-OHDA-induced parkinsonian phenotype by maintaining iron homeostasis. Regulation of MtFt expression in neuronal cells may provide a new neuroprotective strategy for PD.

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Non-transferrin-bound iron (NTBI) overtaken by heart cells might be a key cause leading to iron-mediated injury in heart disorders. NTBI uptake by heart cells might be mediated by divalent metal transporter 1 (DMT1). The understanding of the role of DMT1 in heart iron metabolism is fundamental for elucidating the cause resulting in excessive iron in the heart. The study was to evaluate effects of age and dietary iron on DMT1 mRNA expression and protein synthesis in rat heart. DMT1 mRNA expression was determined by RT-PCR and sequence analysis, and DMT1 protein by Western blot analysis. DMT1 mRNAs with or without iron-responsive element (IRE) both were found in rat heart. Expression of two forms of DMT1 mRNAs was the lowest at the age of post-natal day (PND) 7, and then increased with the age, reaching the highest at PND196 (non-IRE form) and PND63 (IRE form), respectively. During different ages, the levels of DMT1 (IRE) mRNA were higher than those of DMT1 (non-IRE) mRNA and were significantly correlated with the non-heme iron contents in the heart. After fed a high iron for 6 weeks, the rats had a sixfold elevation in heart iron and 22% (non-IRE from) and 40% (IRE from) reduction in DMT1 protein compared to the controls. A low iron diet for 6-weeks caused cardiac hypertrophy and heart iron deficiency and also an increase in levels of two forms of DMT1 proteins. However, iron status had no significant effect on DMT1 (IRE) and DMT1 (non-IRE) mRNAs expression in the heart, although it can significantly influence heart transferrin receptor (TfR) mRNA expression. The results demonstrated that DMT1 mRNAs expression in the heart is age-dependent and that two forms of DMT1 mRNAs both are regulated by iron on the post-transcriptional level only.

Our results show a protective role of MtFt in AD and suggest that regulation of MtFt expression in neuronal cells may provide a new neuroprotective strategy for AD.

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