N6-methyladenosine demethylase FTO regulates neuronal oxidative stress via YTHDC1-ATF3 axis in arsenic-induced cognitive dysfunction,Journal of Hazardous Materials

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N6-methyladenosine demethylase FTO regulates neuronal oxidative stress via YTHDC1-ATF3 axis in arsenic-induced cognitive dysfunction
Journal of Hazardous Materials ( IF 12.2 ) Pub Date : 2024-09-04 , DOI: 10.1016/j.jhazmat.2024.135736
Lixiao Zhou ₁ , Renjie Li ₁ , Fu Wang ₁ , Ruiqi Zhou ₁ , Yinyin Xia ₁ , Xuejun Jiang ₂ , Shuqun Cheng ₁ , Fanghong Wang ₁ , Danyang Li ₁ , Jun Zhang ₃ , Lejiao Mao ₄ , Xuemei Cai ₁ , Hongyang Zhang ₅ , Jingfu Qiu ₅ , Xin Tian ₆ , Zhen Zou ₃ , Chengzhi Chen ₇

Affiliation

Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China.
Center of Experimental Teaching for Public Health, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing 400016, China.
Molecular Biology Laboratory of Respiratory Disease, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China; Research Center for Environment and Human Health, Chongqing Medical University, Chongqing 400016, China.
Molecular Biology Laboratory of Respiratory Disease, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China.
Research Center for Environment and Human Health, Chongqing Medical University, Chongqing 400016, China; Department of Health Laboratory Technology, School of Public Health, Chongqing Medical University, Chongqing 400016, China.
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China; Research Center for Environment and Human Health, Chongqing Medical University, Chongqing 400016, China.

Excessive exposure to metals in daily life has been proposed as an environmental risk factor for neurological disorders. Oxidative stress is an inevitable stage involved in the neurotoxic effects induced by metals, nevertheless, the underlying mechanisms are still unclear. In this study, we used arsenic as a representative environmental heavy metal to induce neuronal oxidative stress and demonstrated that both in vitro and in vivo exposure to arsenic significantly increased the level of N6-methyladenosine (m6A) by down-regulating its demethylase FTO. Importantly, the results obtained from FTO transgenic mice and FTO overexpressed/knockout cells indicated that FTO likely regulated neuronal oxidative stress by modulating activating transcription factor 3 (ATF3) in a m6A-dependent manner. We also identified the specific m6A reader protein, YTHDC1, which interacted with ATF3 and thereby affecting its regulatory effects on oxidative stress. To further explore potential intervention strategies, cerebral metabolomics was conducted and we newly identified myo-inositol as a metabolite that exhibited potential in protecting against arsenic-induced oxidative stress and cognitive dysfunction. Overall, these findings provide new insights into the importance of the FTO-ATF3 signaling axis in neuronal oxidative stress from an m6A perspective, and highlight a beneficial metabolite that can counteract the oxidative stress induced by arsenic.

中文翻译：

N6-甲基腺苷脱甲基酶 FTO 在砷诱导的认知功能障碍中通过 YTHDC1-ATF3 轴调节神经元氧化应激

日常生活中过量接触金属已被提议作为神经系统疾病的环境危险因素。氧化应激是金属诱导的神经毒性作用的必然阶段，然而，其潜在机制尚不清楚。在这项研究中，我们使用砷作为代表性的环境重金属诱导神经元氧化应激，并证明体外和体内暴露于砷都通过下调其去甲基化酶 FTO 显着增加 N6-甲基腺苷（m6A）的水平。重要的是，从 FTO 转基因小鼠和 FTO 过表达/敲除细胞获得的结果表明，FTO 可能通过以 m6A 依赖性方式调节激活转录因子 3 （ATF3）来调节神经元氧化应激。我们还鉴定了特异性 m6A 阅读器蛋白 YTHDC1，它与 ATF3 相互作用，从而影响其对氧化应激的调节作用。为了进一步探索潜在的干预策略，进行了脑代谢组学，我们新发现肌醇是一种代谢物，在防止砷诱导的氧化应激和认知功能障碍方面表现出潜力。总体而言，这些发现从 m6A 的角度为 FTO-ATF3 信号轴在神经元氧化应激中的重要性提供了新的见解，并强调了一种可以抵消砷诱导的氧化应激的有益代谢物。

更新日期：2024-09-04

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