Mitochondrial ferritin in neurodegenerative diseases

Abstract

Mitochondrial ferritin (FtMt) is a novel protein encoded by an intronless gene mapped to chromosome 5q23.1. Ferritin is ubiquitously expressed; however, FtMt expression is restricted to specific tissues such as the testis and the brain. The distribution pattern of FtMt suggests a functional role for this protein in the brain; however, data concerning the roles of FtMt in neurodegenerative diseases remain scarce. In the human cerebral cortex, FtMt expression was increased in Alzheimer's disease patients compared to control cases. Cultured neuroblastoma cells showed low-level expression of FtMt, which was increased by H2O2 treatment. FtMt overexpression showed a neuroprotective effect against H2O2-induced oxidative stress and Aβ-induced neurotoxicity in neuroblastoma cells. FtMt expression was also detected in dopaminergic neurons in the substantia nigra and was increased in patients with restless legs syndrome, while FtMt had a protective effect against cell death in a neuroblastoma cell line model of Parkinson's disease. FtMt is involved in other neurodegenerative diseases such as age-related macular degeneration (AMD), with an FtMt gene mutation identified in AMD patients, and Friedreich's ataxia, which is caused by a deficiency in frataxin. FtMt overexpression in frataxin-deficient cells increased cell resistance to H2O2 damage. These results implicate a neuroprotective role of FtMt in neurodegenerative diseases.

Mitoferrin modulates iron toxicity in a Drosophila model of Friedreich׳s ataxia

“…In agreement with this hypothesis, elevated doses of deferiprone gradually affect aconitase activity in cultured skin fibroblasts from FRDA and healthy controls [67]. Moreover, mitochondrial ferritin causes iron relocation in the mitochondria that triggers a simultaneous reduction of cytosolic iron and of ferritin expression [68]. This would explain the inefficiency of Fer3HCH overexpression to rectify ferritin levels in frataxin-deficient flies.…”

The Role of PICALM in Alzheimer’s Disease

“…In accordance with this hypothesis, it has been found that huperzine A (an anti-AD drug in China) inhibits the rising level of iron in CNS, as well as the expression of transferrin-receptor 1 and the transferrin-bound iron uptake in cultured neurons [131]. On the other hand, mitochondrial ferritin has been implicated in the protective mechanism of AD [132,133]. Moreover, anemia [134] and iron level in diet [135] have also been linked to AD prevalence.…”

The Protective Role of Mitochondrial Ferritin on Erastin-Induced Ferroptosis

“…Previous studies suggested that overexpression of FtMt caused redistribution of iron from cytosol to mitochondria (Nie et al, 2005), thus high levels of FtMt in mitochondria may prevent cytosolic iron accumulation. Our previous studies have found that FtMt overexpression in neuroblastoma SH-SY5Y cell increased its resistance to oxidative stress (Shi et al, 2010; Wu et al, 2013), indicating FtMt is not only involved in storing cellular iron, but may also play a role in protecting mitochondria from iron-dependent oxidative damage (Yang et al, 2013; Gao and Chang, 2014). Our recent studies showed that FtMt overexpression protected 6-hydroxydopamine-indeced dopaminergic cell damage (You et al, 2016), and FtMt played inhibitory effects on neuronal tumor cell proliferation (Shi et al, 2015).…”