2. Academic Validation
  3. ALKBH5-mediated N6-methyladenosine modification of HO-1 mRNA regulates ferroptosis in cobalt-induced neurodegenerative damage

ALKBH5-mediated N6-methyladenosine modification of HO-1 mRNA regulates ferroptosis in cobalt-induced neurodegenerative damage

  • Environ Int. 2024 Aug:190:108897. doi: 10.1016/j.envint.2024.108897.
Qianqian Su 1,  Lingyan Wu 1,  Chunyan Zheng 2,  Xianqi Ji 1,  Xinpei Lin 1,  Yu Zhang 1,  Fuli Zheng 1,  Zhenkun Guo 1,  Wenya Shao 1,  Hong Hu 1,  Jinfu Zhou 3,  Yu Jiang 1,  Ying Tang 4,  Siying Wu 5,  Michael Aschner 6,  Huangyuan Li 7,  Guangxia Yu 8
Affiliations

Affiliations

  • 1 The Key Laboratory of Environment and Health, Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou 350122, China.
  • 2 Fujian Maternity and Child Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350001, Fujian Province, China.
  • 3 The Key Laboratory of Environment and Health, Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou 350122, China; Fujian Maternity and Child Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350001, Fujian Province, China.
  • 4 Fujian Center for Prevention and Control Occupational Diseases and Chemical Poisoning, Fuzhou 350125, China.
  • 5 Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou 350122, China.
  • 6 Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. Electronic address: michael.aschner@einsteinmed.org.
  • 7 The Key Laboratory of Environment and Health, Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou 350122, China. Electronic address: lhy@fjmu.edu.cn.
  • 8 The Key Laboratory of Environment and Health, Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou 350122, China. Electronic address: guangxiayu@fjmu.edu.cn.
PMID: 39047545 DOI: 10.1016/j.envint.2024.108897
Abstract

The utilization of Cobalt (Co) has surged due to it is critical role in renewable energy technologies and other high-tech applications. Concurrently, the potential health risks associated with Co exposure have raised concerns. Previous studies, including our own, have shown that Co can impair learn and memory functions as an epigenetic hazard, even at low concentrations. In this study, we explore the mechanisms of Co-induced Ferroptosis in neurodegenerative damage both in vivo and in vitro, focusing on the epigenetic regulation by N6-methyladenosine (m6A) demethylase alkB homolog 5 (ALKBH5). We identify heme oxygenase-1 (HO-1) as a direct target gene of ALKBH5, playing a crucial role in mitigating Co-induced Ferroptosis. ALKBH5 deficiency affects the post-transcriptional regulation of HO-1 through m6A modification, which in turn influences mRNA's stability, intracellular distribution, and alternative splicing, thereby enhancing susceptibility to Co-induced Ferroptosis. Additionally, we discuss the potential involvement of heterogeneous nuclear ribonucleoprotein M (hnRNPM) in regulating alternative splicing of HO-1 mRNA, potentially mediated by m6A modifications. This study provides new epigenetic insights into the post-transcriptional regulatory mechanisms involved in Co-induced Ferroptosis and highlights the broader implications of environmental hazards in neurodegenerative damage.

Keywords

Cobalt; Epigenetic hazard; Ferroptosis; N6-methyladenosine demethylase; Neurodegenerative damage.

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