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  3. Manganese overexposure results in ferroptosis through the HIF-1α/p53/SLC7A11 pathway in ICR mouse brain and PC12 cells

Manganese overexposure results in ferroptosis through the HIF-1α/p53/SLC7A11 pathway in ICR mouse brain and PC12 cells

  • Ecotoxicol Environ Saf. 2024 May 22:279:116481. doi: 10.1016/j.ecoenv.2024.116481.
Jian Chen 1,  Zehua Tao 1,  Xinyu Zhang 1,  Jing Hu 1,  Suhua Wang 1,  Guangwei Xing 1,  Ngwa Adeline Ngeng 1,  Abdul Malik 2,  Kwaku Appiah-Kubi 3,  Marcelo Farina 4,  Anatoly V Skalny 5,  Alexey Tinkov 5,  Michael Aschner 6,  Bobo Yang 7,  Rongzhu Lu 8
Affiliations

Affiliations

  • 1 Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China.
  • 2 Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China; Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province 212001, China.
  • 3 Department of Applied Biology, C. K. Tedam University of Technology and Applied Sciences, Navrongo UK-0215-5321, Ghana.
  • 4 Department of Biochemistry, Federal University of Santa Catarina, Florianópolis, Santa Catarina 88040-900, Brazil.
  • 5 Laboratory of Molecular Dietetics, IM Sechenov First Moscow State Medical University (Sechenov University), Bolshaya Pirogovskaya St., 2-4, Moscow 119146, Russia; Orenburg State University, Pobedy Ave.13, Orenburg 460018, Russia.
  • 6 Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • 7 Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China. Electronic address: boboyang93@163.com.
  • 8 Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China; Experimental Research Center, Affiliated Kunshan Hospital, Jiangsu University, Kunshan, Jiangsu 215300, China. Electronic address: lurz@ujs.edu.cn.
PMID: 38788562 DOI: 10.1016/j.ecoenv.2024.116481
Abstract

Manganese (Mn) overexposure has been associated with the development of neurological damage reminiscent of Parkinson's disease, while the underlying mechanisms have yet to be fully characterized. This study aimed to investigate the mechanisms leading to injury in dopaminergic neurons induced by Mn and identify novel treatment approaches. In the in vivo and in vitro models, ICR mice and dopaminergic neuron-like PC12 cells were exposed to Mn, respectively. We treated them with anti-ferroptotic agents ferrostatin-1 (Fer-1), deferoxamine (DFO), HIF-1α activator dimethyloxalylglycine (DMOG) and inhibitor LW6. We also used p53-siRNA to verify the mechanism underlying Mn-induced neurotoxicity. Fe and Mn concentrations increased in ICR mice brains overexposed to Mn. Additionally, Mn-exposed mice exhibited movement impairment and encephalic pathological changes, with decreased HIF-1α, SLC7A11, and GPX4 proteins and increased p53 protein levels. Fer-1 exhibited protective effects against Mn-induced both behavioral and biochemical changes. Consistently, in vitro, Mn exposure caused ferroptosis-related changes and decreased HIF-1α levels, all ameliorated by Fer-1. Upregulation of HIF-1α by DMOG alleviated the Mn-associated Ferroptosis, while LW6 exacerbated Mn-induced neurotoxicity through downregulating HIF-1α. p53 knock-down also rescued Mn-induced Ferroptosis without altering HIF-1α protein expression. Mn overexposure resulted in Ferroptosis in dopaminergic neurons, mediated through the HIF-1α/p53/SLC7A11 pathway.

Keywords

Dimethyloxalylglycine (DMOG); Ferroptosis; HIF-1α; Manganese chloride; p53.

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