Date Published: July 21, 2017
Publisher: JKL International LLC
Author(s): Guofen Gao, Nan Zhang, Yue-Qi Wang, Qiong Wu, Peng Yu, Zhen-Hua Shi, Xiang-Lin Duan, Bao-Lu Zhao, Wen-Shuang Wu, Yan-Zhong Chang.
Oxidative stress and iron accumulation are tightly associated with neurodegenerative diseases. Mitochondrial ferritin (FtMt) is identified as an iron-storage protein located in the mitochondria, and its role in regulation of iron hemeostasis in neurodegenerative diseases has been reported. However, the role of FtMt in hydrogen peroxide (H2O2)-induced oxidative stress and iron accumulation in neuronal cells has not been studied. Here, we overexpressed FtMt in neuroblastoma SH-SY5Y cells and induced oxidative stress by treating with extracellular H2O2. We found that overexpression of FtMt significantly prevented cell death induced by H2O2, particularly the apoptosis-dependent cell death. The protective effects involved inhibiting the generation of cellular reactive oxygen species, sustaining mitochondrial membrane potential, maintaining the level of anti-apoptotic protein Bcl-2, and inhibiting the activation of pro-apoptotic protein caspase 3. We further explored the mechanism of these protective effects and found that FtMt expression markedly altered iron homeostasis of the H2O2 treated cells as compared to that of controls. The FtMt overexpression significantly reduced cellular labile iron pool (LIP) and protected H2O2-induced elevation on LIP. While in H2O2 treated SH-SY5Y cells, the increased iron uptake and reduced iron release, in correlation with levels of DMT1(-IRE) and ferroportin 1, resulted in heavy iron accumulation, the FtMt overexpressing cells didn’t show any significant changes in levels of iron transport proteins and in the level of LIP. These results implicate a neuroprotective role of FtMt on H2O2-induced oxidative stress, which may provide insights into the treatment of iron accumulation associated neurodegenerative diseases.
At normal condition, cells were in a balance between ROS and antioxidant. Once the balance was disrupted, cells would be exposed to oxidative stress damage. ROS destroys the enzymes in cytosol, induces lipid peroxidation, decreases MMP, and further leads to cell apoptosis. Iron is one of the important activators that lead to oxidative stress damage [6, 46]. Thus, the iron level in the body is under strict control, and dysregulation of iron homeostasis could cause severe diseases. FtMt, as an iron-storage protein in mitochondria, has been reported to be involved in iron redistribution from cytosol to mitochondria [15, 16, 20]. Recently, FtMt was mainly recognized for its protective role in diseases associated with iron-dependent oxidative damage [23-25, 27-29], although that FtMt sensitized cells to oxidative stress was also reported . Our previous studies have indicated the neuroprotective role of FtMt in Parkinson’s disease and Alzheimer’s disease [23, 27]. In this study, we explored the effects of FtMt on H2O2 induced neuronal cell damage and further investigated FtMt’s functions at the molecular level.