Ferroptosis, a newly identified form of regulated cell death, is characterized by overwhelming iron-dependent accumulation of lethal lipid reactive oxygen species (ROS). Preventing cellular iron overload by reducing iron uptake and increasing iron storage may contribute to inhibit ferroptosis. Mitochondrial ferritin (FtMt) is an iron-storage protein that is located in the mitochondria, which has a significant role in modulating cellular iron metabolism. Recent studies showed that FtMt played inhibitory effects on oxidative stress-dependent neuronal cell damage. However, the potential role of FtMt in the progress of ferroptosis in neuronal cells has not been studied. To explore this, we established ferroptosis models of cell and drosophila by erastin treatment. We found that overexpression of FtMt in neuroblastoma SH-SY5Y cells significantly inhibited erastin-induced ferroptosis, which very likely was achieved by regulation of iron homeostasis. Upon erastin treatment, significant increases of cellular labile iron pool (LIP) and cytosolic ROS were observed in wild-type SH-SY5Y cells, but not in the FtMt-overexpressed cells. Consistent with that, the alterations of iron-related proteins in FtMt-overexpressed cells were different from that of the control cells. We further investigated the role of FtMt in erastin-induced ferroptosis in transgenic drosophila. We found that the wild-type drosophilas fed an erastin-containing diet didn't survive more than 3 weeks. In contrast, the FtMt overexpressing drosophilas fed the same diet were survival very well. These results indicated that FtMt played a protective role in erastin-induced ferroptosis.
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Inflammatory responses involving microglia and astrocytes contribute to the pathogenesis of neurodegenerative diseases (NDs). In addition, inflammation is tightly linked to iron metabolism dysregulation. However, it is not clear whether the brain inflammation-induced iron metabolism dysregulation contributes to the NDs pathogenesis. Herein, we demonstrate that the expression of the systemic iron regulatory hormone, hepcidin, is induced by lipopolysaccharide (LPS) through the IL-6/STAT3 pathway in the cortex and hippocampus. In this paradigm, activated glial cells are the source of IL-6, which was essential in the iron overload-activated apoptosis of neurons. Disrupting astrocyte hepcidin expression prevented the apoptosis of neurons, which were able to maintain levels of FPN1 adequate to avoid iron accumulation. Together, our data are consistent with a model whereby inflammation initiates an intercellular signaling cascade in which activated microglia, through IL-6 signaling, stimulate astrocytes to release hepcidin which, in turn, signals to neurons, via hepcidin, to prevent their iron release. Such a pathway is relevant to NDs in that it links inflammation, microglia and astrocytes to neuronal damage.
Ischaemic stroke is becoming the most common cerebral disease in aging populations, but the underlying molecular mechanism of the disease has not yet been fully elucidated. Increasing evidence has indicated that an excess of iron contributes to brain damage in cerebral ischaemia/reperfusion (I/R) injury. Although mitochondrial ferritin (FtMt) plays a critical role in iron homeostasis, the molecular function of FtMt in I/R remains unknown. We herein report that FtMt levels are upregulated in the ischaemic brains of mice. Mice lacking FtMt experience more severe brain damage and neurological deficits, accompanied by typical molecular features of ferroptosis, including increased lipid peroxidation and disturbed glutathione (GSH) after cerebral I/R. Conversely, FtMt overexpression reverses these changes. Further investigation shows that Ftmt ablation promotes I/R-induced inflammation and hepcidin-mediated decreases in ferroportin1, thus markedly increasing total and chelatable iron. The elevated iron consequently facilitates ferroptosis in the brain of I/R. In brief, our results provide evidence that FtMt plays a critical role in protecting against cerebral I/R-induced ferroptosis and subsequent brain damage, thus providing a new potential target for the treatment/prevention of ischaemic stroke.
Mitochondrial ferritin (FtMt) is a novel iron-storage protein in mitochondria. Evidences have shown that FtMt is structurally and functionally similar to the cytosolic H-chain ferritin. It protects mitochondria from iron-induced oxidative damage presumably through sequestration of potentially harmful excess free iron. It also participates in the regulation of iron distribution between cytosol and mitochondrial contents. Unlike the ubiquitously expressed H-ferritin, FtMt is mainly expressed in testis and brain, which suggests its tissue-related roles. FtMt is involved in pathogenesis of neurodegenerative diseases, as its increased expression has been observed in Alzheimer’s disease, restless legs syndrome and Friedreich’s ataxia. Studies from our laboratory showed that in Alzheimer’s disease, FtMt overexpression attenuated the β-amyloid induced neurotoxicity, which on the other hand increased significantly when FtMt expression was knocked down. It is also found that, by maintaining mitochondrial iron homeostasis, FtMt could prevent 6-hydroxydopamine induced dopaminergic cell damage in Parkinson’s disease. These recent findings on FtMt regarding its functions in regulation of brain iron homeostasis and its protective role in pathogenesis of neurodegenerative diseases are summarized and reviewed.
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