2. Academic Validation
  3. Selenium restored mitophagic flux to alleviate cadmium-induced hepatotoxicity by inhibiting excessive GPER1-mediated mitophagy activation

Selenium restored mitophagic flux to alleviate cadmium-induced hepatotoxicity by inhibiting excessive GPER1-mediated mitophagy activation

  • J Hazard Mater. 2024 Aug 15:475:134855. doi: 10.1016/j.jhazmat.2024.134855.
Honglong Zhang 1,  Jun Yan 2,  Danna Xie 1,  Xingwang Zhu 1,  Guole Nie 1,  Haijun Zhang 3,  Xun Li 4
Affiliations

Affiliations

  • 1 The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, Gansu, People's Republic of China.
  • 2 The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, Gansu, People's Republic of China; Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu, People's Republic of China; Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, Gansu, People's Republic of China; Medical School Cancer Center of Lanzhou University, Lanzhou 730000, Gansu, People's Republic of China; Hepatopancreatobiliary Surgery Institute of Gansu Province, Lanzhou 730000, Gansu, People's Republic of China.
  • 3 Department of Anesthesiology and Operating Theater, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu, People's Republic of China.
  • 4 The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, Gansu, People's Republic of China; Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu, People's Republic of China; Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, Gansu, People's Republic of China; Medical School Cancer Center of Lanzhou University, Lanzhou 730000, Gansu, People's Republic of China; Hepatopancreatobiliary Surgery Institute of Gansu Province, Lanzhou 730000, Gansu, People's Republic of China; General Surgery Clinical Medical Research Center of Gansu Province, Lanzhou 730000, Gansu, People's Republic of China. Electronic address: lxdr21@126.com.
PMID: 38880044 DOI: 10.1016/j.jhazmat.2024.134855
Abstract

Cadmium (Cd) is a common environmental pollutant, while selenium (Se) can ameliorate heavy metal toxicity. Consequently, this study aimed to investigate the protective effects of Se against Cd-induced hepatocyte injury and its underlying mechanisms. To achieve this, we utilized the Dongdagou-Xinglong cohort, BRL3A cell models, and a rat model exposed to Cd and/or Se. The results showed that Se counteracted liver function injury and the decrease in GPER1 levels caused by environmental Cd exposure, and various methods confirmed that Se could protect against Cd-induced hepatotoxicity both in vivo and in vitro. Mechanistically, Cd caused excessive Mitophagy activation, evidenced by the colocalization of LC3B, PINK1, Parkin, p62, and TOMM20. Transfection of BRL3A cells with mt-keima adenovirus indicated that Cd inhibited autophagosome-lysosome fusion, thereby impeding mitophagic flux. Importantly, G1, a specific agonist of GPER1, mitigated Cd-induced Mitophagy overactivation and hepatocyte toxicity, whereas G15 exacerbates these effects. Notably, Se supplementation attenuated Cd-induced GPER1 protein reduction and excessive Mitophagy activation while facilitating autophagosome-lysosome fusion, thereby restoring mitophagic flux. In conclusion, this study proposed a novel mechanism whereby Se alleviated GPER1-mediated Mitophagy and promoted autophagosome-lysosome fusion, thus restoring Cd-induced mitophagic flux damage, and preventing hepatocyte injury.

Keywords

Cadmium; GPER1; Hepatotoxicity; Mitophagy; Selenium.

Figures
Products