Mechanistic basis for impaired ferroptosis in cells expressing the African-centric S47 variant of p53

Abstract

A population-restricted single-nucleotide coding region polymorphism (SNP) at codon 47 exists in the human TP53 gene (P47S, hereafter P47 and S47). In studies aimed at identifying functional differences between these variants, we found that the Africanspecific S47 variant associates with an impaired response to agents that induce the oxidative stress-dependent, nonapoptotic cell death process of ferroptosis. This phenotype is manifested as a greater resistance to glutamate-induced cytotoxicity in cultured cells as well as increased carbon tetrachloride-mediated liver damage in a mouse model. The differential ferroptotic responses associate with intracellular antioxidant differences between P47 and S47 cells, including elevated abundance of the low molecular weight thiols coenzyme A (CoA) and glutathione in S47 cells. Importantly, the disparate ferroptosis phenotypes related to the P47S polymorphism are reversible. Exogenous administration of CoA provides protection against ferroptosis in cultured mouse and human cells, as well as in a mouse model. The combined data support a positive role for p53 in ferroptosis and identify CoA as a regulator of this cell death process. Together, these findings provide mechanistic insight linking redox regulation of p53 to small molecule antioxidants and stress signaling pathways. They also identify potential therapeutic approaches to redox-related pathologies.p53 | coenzyme A | ferroptosis | S-thiolation | polymorphism

Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases

“…Lipid peroxidation also happened in p53-mediated ferroptosis. P53 plays a positive role in ferroptosis and identifies coenzyme A (CoA) as a regulator of this cell death process (Leu et al, 2019). Loss of P53 prevents nuclear accumulation of dipeptidyl-peptidase-4 (DPP4) and thus facilitates plasma membrane-associated DPP4-dependent lipid peroxidation, which finally results in ferroptosis (Xie et al, 2017), and p53 suppresses ferroptosis through the induction of cyclindependent kinase inhibitor 1A (CDKN1A/p21) expression by reduced accumulation of toxic lipid-ROS (Tarangelo et al, 2018;Kang et al, 2019).…”

Increased mTOR activity and metabolic efficiency in mouse and human cells containing the African-centric tumor-predisposing p53 variant Pro47Ser

“…The animals also display signs 267 of superior fitness. The enhanced mTOR activity is due in part to the higher levels of GSH in S47 268 cells and tissues, which we previously reported (Leu et al, 2019). The increased GSH results in 269 impaired ability of the redox sensitive protein GAPDH to bind to Rheb.…”

“…These data suggest that free sulfhydryls are different in WT 229 and S47 cells and tissues, possibly due to the increased GSH in S47 cells. To test this premise 230 further we pre-treated WT and S47 MEFs with the compound diethylmaleate (DEM), which 231 decreases the level of reduced GSH in cells (Leu et al, 2019). We found that pre-treatment of 232 cells with DEM restores the mobility of GAPDH in S47 cells to that evident in cells with WT p53 233 ( Figure 5E).…”

The emerging role of ferroptosis in non-cancer liver diseases: hype or increasing hope?

“…Erastin is capable of reducing GSH level by repressing system x c − activity and activating the endoplasmic reticulum (ER) stress response, favoring ROS accumulation in ferroptotic process 27 . Moreover, p53 has been proved to downregulate system x c − expression resulting in cystine starvation and susceptibility to ferroptosis, thereby probably being beneficial for cancer eradication 28,29 .…”