Abstract
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.
Highlights
The small molecule erastin triggers a unique iron-dependent form of non-apoptotic cell death in cancer cells and certain normal cells, which was recently identified as ferroptosis (Dixon et al, 2012)
We found that overexpression of Mitochondrial ferritin (FtMt) in neuroblastoma SH-SY5Y cells significantly inhibited erastin-induced ferroptosis, which very likely was achieved by regulation of iron homeostasis
Studies have shown that the ferroptosis process could be blocked by iron chelators, while it was enhanced by exogenous lysosomal form of iron (Dixon et al, 2012; Eling et al, 2015)
Summary
The small molecule erastin triggers a unique iron-dependent form of non-apoptotic cell death in cancer cells and certain normal cells, which was recently identified as ferroptosis (Dixon et al, 2012). Ferroptosis is morphologically, biochemically and genetically distinct from apoptosis, necrosis and autophagy, as it is characterized by the overwhelming iron-dependent accumulation of lethal lipid reactive oxygen species (ROS) (Dixon et al, 2012; Xie et al, 2016). The Abbreviations: FtMt, Mitochondrial ferritin; LIP, cellular labile iron pool; ROS, reactive oxygen species; NADPH, nicotinamide adenine dinucleotide phosphate; NOX, NADPH-dependent oxidase; IRP2, iron regulator protein 2; TfR1, transferrin receptor 1; VDAC, voltage-dependent anion channels. FtMt Protects Erastin-Induced Ferroptosis generation of ROS involves nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidase (NOX) family of superoxide-producing enzymes and lipid peroxidation. IRP2 expression decreases iron uptake by reducing transferrin receptor (TfR) expression and increases free iron storage by inducing ferritin expression (Henderson and Kühn, 1995; Schneider and Leibold, 2000; Meyron-Holtz et al, 2004). Reducing iron uptake and/or increasing iron storage may potentially inhibit ferroptosis
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