P53-mediated ferroptosis is required for 1-methyl-4-phenylpyridinium-induced senescence of PC12 cells. (June 2021)

• Record Type: Journal Article
• Authors: Li, Shanshan; Wang, Meng; Wang, Youlin; Guo, Yuting; Tao, Xiaoxiao; Wang, Xuncui; Cao, Yin; Tian, Shasha; Li, Qinglin
• Is Part Of: Toxicology in vitro. Volume 73(2021)
• Publication Date: 2021-06
• Subjects: Ferroptosis -- Senescence -- Parkinson's disease; 3-MA 3-methyladenine -- ACSL4 acyl-CoA synthetase long chain family member 4 -- DFO deferoxamine -- DNs dopaminergic neurons -- Fer-1 ferrostatin-1 -- FTH1 ferritin heavy chain 1 -- GPX4 glutathione peroxidase 4 -- GSH glutathione -- MDA malondialdehyde -- MMP mitochondrial membrane potential -- MPP+ 1-methyl-4-phenylpyridinium -- MPTP 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine -- PD Parkinson's disease -- SA-β-gal senescence-associated β-galactosidase -- SOD superoxide dismutase -- SLC7A11 solute carrier family 7 member 11 -- Z-VAD-FMK carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone; Toxicity testing -- In vitro -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1016/j.tiv.2021.105146
• Languages: English
• ISSNs: 0887-2333

Abstract

Abstract: Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra and striatum. Aging is the most important risk factor of PD. Ferroptosis is an iron-dependent form of cell death associated with PD. However, it is not clear whether ferroptosis accelerates PD by promoting cellular senescence. This study investigated the mechanism of 1-methyl-4-phenylpyridinium (MPP + ) -induced PC12 cells injury. We found that MPP + induced cell senescence with increased β-galactosidase activity and the expression of p53, p21 and p16 activation in cells. In addition, MPP + treatment showed smaller mitochondria and increased membrane density, downregulation of ferritin heavy chain 1 expression and upregulation of acyl-CoA synthetase long chain family member 4 expression, and enhanced levels of oxidative stress, which were important characteristics of ferroptosis. Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, was tested to eliminate MPP + -induced cell senescence. Fer-1 downregulated the expression of p53 and upregulated the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase-4 (GPX4) in MPP + -induced ferroptosis. Inhibition of p53 eliminated cell senescence by upregulation the expression of of SLC7A11 and GPX4. Thus, these results suggest that MPP + induces senescence in PC12 cells via the p53/ SLC7A11/ GPX4 signaling pathway in the ferroptosis regulation mechanism. Highlights: MPP + induced cell senescence with increased β-galactosidase activity and the expression of p53, p21 and p16 activation in PC12 cells. MPP + induced ferroptosis was related to increased oxidative stress and p53/ SLC7A11/ GPX4 signaling pathway. Inhibition of p53 eliminated cell senescence by ferroptosis regulation mechanism in MPP + -induced PC12 cells.