Manganese triggers persistent activation of the integrated stress response by inhibition of SIRT1 on deacetylation of GADD34

• Published in: The Science of the total environment Vol. 887; p. 164124
• Main Authors: Jia, Yunfei, Ma, Xiaofan, He, Bin, Liu, Zhuofan, Liu, Kuan, Ma, Zhuo, Liu, Wei, Xu, Bin
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 20.08.2023
• Subjects: Animals; Apoptosis; Integrated stress response; Manganese; Manganese - pharmacology; Mice; Phosphorylation; Proteins - metabolism; Signal Transduction; Sirtuin 1; Sirtuin 1 - metabolism; Integrated stress response; Sirtuin 1; Manganese; Apoptosis
• ISSN: 0048-9697; 1879-1026
• DOI: 10.1016/j.scitotenv.2023.164124

Overexposure to manganese (Mn) is conducive to neurodegenerative diseases and neuronal injury. Persistent activation of the integrated stress response (ISR) has a substantial impact on the etiology of neurodegenerative disorders by interfering with intracellular homeostasis. Nevertheless, the precise mechanism through which ISR engages in Mn-related neurotoxicity remains unclear. Sirtuin 1 (SIRT1), a typical NAD+-dependent protein deacetylase, which is known to participate in Mn-induced neuronal damage. Therefore, the aim of our study was to clarify how SIRT1 regulates persistent ISR activation in mouse hippocampal neuronal cells (HT-22 cells) exposed to various concentrations of Mn. We discovered that persistent ISR activation was engaged in Mn-triggered mitochondrial and exogenous apoptotic signaling pathways, which was attributed to the excessive phosphorylation of eukaryotic translation initiation factor 2α (eIF2α). Growth arrest and DNA damage-inducible protein 34 (GADD34) is known to be responsible for down-regulating the phosphorylation of eIF2α. However, Mn promoted GADD34 protein expression and its acetylation level. We further investigated the effect of SIRT1 on the acetylation of GADD34 by overexpressing and silencing SIRT1. We discovered that SIRT1 activation significantly declined the acetylation level of GADD34, thus alleviating persistent ISR activation-mediated neuronal apoptosis in HT-22 cells-treated with Mn. In summary, these results suggested that Mn induced persistent activation of the ISR by inhibition of SIRT1 on deacetylation of GADD34. [Display omitted] •ISR was involved in Mn-induced neuronal apoptosis.•The persistent ISR activation was attributed to excessive eIF2α phosphorylation.•Mn suppressed the ability of SIRT1 to deacetylate GADD34 protein.•SIRT1 activation mitigated the acetylation of GADD34 triggered by Mn.