The Protective Role of Mitochondrial Ferritin on Erastin-Induced Ferroptosis

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.

Rapid Assessment of Mitochondrial Complex I Activity and Metabolic Phenotyping of Breast Cancer Cells by NAD(p)H Cytometry

“…As can be seen in Figure 3d, 20 h treatment with 20 μM erastin leads to a significant reduction in {Δψ m / NAD(p)H} ratio of MDA231 while this ratio was unaltered in MCF7 cells. Figure 3e shows that erastin treatment is accompanied by a significant increase in ROS generation in MDA231 cells (and not in MCF7 cells) which concurs with earlier published studies on the mechanism of action for this small molecule drug (38,39,41). Together, this result points to the fact that {Δψ m /NAD(p)H} ratio is a reliable indicator of drug sensitivity and in this particular example, the changes in this metric might be associated with the excessive ROS generated by erastin in MDA231 cells.…”

“…After confirming that these two cells have similar rotenone sensitivity, we next asked if the {Δψ m /NAD(p)H} ratio can reliably report differential drug sensitivity between these two cell lines. Toward this, we chose a small molecule drug, erastin that has been earlier shown to cause cytotoxicity only in cancer cells with mutations in Rasoncogene (36)(37)(38)(39)(40). MDA231 cells have been reported to display Ras-mutations while MCF7 cells are known to have wild-type Ras.…”

Vitamin E deficiency during embryogenesis in zebrafish causes lasting metabolic and cognitive impairments despite refeeding adequate diets

“…A unifying mechanism potentially linking developmental VitE deficiency with many of the metabolic perturbations reported herein – all of which may perturb brain function – is ferroptosis, a process of non-apoptotic programmed cell death [51] that involves several key features observed in our E− larvae, most critically: 1) enhanced enzymatic lipid peroxidation [52], especially due to excessive ARA metabolism via 5- [53] and 15-lipooxygenase [54] activities (Figure 6A-B; including 5- and 15-HETE; 5-oxo-ETE [55]); 2) glutathione depletion [56] (Figure 7); and 3) mitochondrial dysfunction [57] (Figure 10). We also found E− larvae had increased levels of glutamate (p< 0.001; Supplementary Table 1) relative to E+ larvae, which could signify glutamate toxicity, another metabolic perturbation associated with ferroptosis [53] via inhibition of the cellular cysteine/glutamate antiporter system X c - [51].…”

Nexus between mitochondrial function, iron, copper and glutathione in Parkinson's disease

“…Elevated mitochondrial iron causes oxidative stress, impairs mitochondrial function and leads to neuronal death (Munoz et al, 2016). Sequestering mitochondrial iron by overexpression of mitochondrial ferritin protects neuronal cells from multiple mitochondrial toxins in vitro (Shi et al, 2010;Wang et al, 2016;You et al, 2016).…”