Induction of mitophagy via ROS-dependent pathway protects copper-induced hypothalamic nerve cell injury

Song Zhu; Hongbin Wu; Hengmin Cui; Hongrui Guo; Yujuan Ouyang; Zhihua Ren; Youtian Deng; Yi Geng; Ping Ouyang; Aimin Wu; Junliang Deng; Huidan Deng

doi:10.1016/j.fct.2023.114097

Induction of mitophagy via ROS-dependent pathway protects copper-induced hypothalamic nerve cell injury

Food Chem Toxicol. 2023 Nov:181:114097. doi: 10.1016/j.fct.2023.114097. Epub 2023 Oct 13.

Authors

Song Zhu¹, Hongbin Wu², Hengmin Cui³, Hongrui Guo¹, Yujuan Ouyang¹, Zhihua Ren¹, Youtian Deng⁴, Yi Geng¹, Ping Ouyang¹, Aimin Wu¹, Junliang Deng⁵, Huidan Deng⁶

Affiliations

¹ College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu, 611130, China.
² The Experimental Animal Center of West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
³ College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu, 611130, China; Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu, 611130, China; Key Laboratory of Agricultural Information Engineering of Sichuan Province, Sichuan Agriculture University, Yaan, Sichuan, 625014, China.
⁴ College of Food Science, Sichuan Agriculture University, Yaan, Sichuan, 625014, China.
⁵ College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu, 611130, China; Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu, 611130, China. Electronic address: dengjl213@126.com.
⁶ College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu, 611130, China; Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu, 611130, China. Electronic address: denghuidan@sicau.edu.cn.

PMID: 37839787
DOI: 10.1016/j.fct.2023.114097

Abstract

Copper (Cu) is one of the essential trace elements in the body, but excessive amounts of Cu harm multiple organs and tissues such as liver, kidneys, testis, ovaries, and brain. However, the mechanism of hypothalamic neurotoxicity induced by Cu is still unknown. This study examined the relationship between reactive oxygen species (ROS) and mitophagy in mouse hypothalamus treated with high Cu. The results demonstrated that high levels of copper sulfate (CuSO₄) could cause histopathological and neuronal changes in the mouse hypothalamus, produce a large amount of ROS, induce mitophagy, and lead to an imbalance of mitochondrial fusion/fission. The main manifestations are an increase in the expression levels of LC3-II/LC3-I, p62, DRP1, and FIS1, and a decrease in the expression levels of MFN1 and MFN2. Cu can induce mitophagy also was confirmed by LC3 co-localization with TOMM20 (mitochondrial marker). Next, the effect of oxidative stress on CuSO₄-induced mitophagy was demonstrated. The results showed that ROS inhibitor N-acetylcysteine (NAC) diminished CuSO₄-induced mitophagy and reversed the disturbance of mitochondrial dynamics. Additionally, a study was carried out to evaluate the role of mitophagy in CuSO₄-induced hypothalamic injury. The inhibition of mitophagy using mitophagy inhibitor (Mdivi-1) decreased cell viability and promoted CuSO₄-inhibited mitochondrial fusion. The aforementioned results suggested that CuSO₄ induced mitophagy via oxidative stress in N38 cells and mouse hypothalamus, and that the activation of mitophagy might generate protective mechanisms by alleviating Cu-induced mitochondrial dynamics disorder. This study provided a novel approach and theoretical basis for studying and preventing Cu neurotoxicity.

Keywords: CuSO(4); Hypothalamic; Mitophagy; Mouse; ROS.

MeSH terms

Animals
Copper / toxicity
Male
Mice
Mitochondrial Diseases*
Mitophagy*
Neurons / metabolism
Reactive Oxygen Species / metabolism

Substances

Copper
Reactive Oxygen Species
3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone