Evidence from an Avian Embryo Model that Zinc-Inducible MT4 Expression Protects Mitochondrial Function Against Oxidative Stress

文献类型： 外文期刊

第一作者： Li, Hao

作者： Li, Hao;Gao, Wei;Wang, Heng;Huang, Liang;Yuan, Tong;Zheng, Wenxuan;Wu, Qilin;Wang, Wence;Yang, Lin;Zhu, Yongwen;Zhang, Huaqi;Liu, Ju;Xu, Weihan

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关键词： avian embryo model; metallothionein; mitochondrial function; oxidative stress; zinc

期刊名称：JOURNAL OF NUTRITION （ 影响因子：4.2； 五年影响因子：4.7 ）

ISSN： 0022-3166

年卷期： 2024 年 154 卷 3 期

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收录情况： SCI

摘要： Background: Metallothioneins (MTs) have a strong affinity for zinc (Zn) and remain at a sufficiently high level in mitochondria. As the avian embryo is highly susceptible to oxidative damage and relatively easy to manipulate in a naturally closed chamber, it is an ideal model of the effects of oxidative stress on mitochondrial function. However, the protective roles and molecular mechanisms of Zn-inducible protein expression on mitochondrial function in response to various stressors are poorly understood. Objectives: The study aimed to investigate the mechanisms by which Zn-induced MT4 expression protects mitochondrial function and energy metabolism subjected to oxidative stress using the avian embryo and embryonic primary hepatocyte models. Methods: First, we investigated whether MT4 expression alters mitochondrial function. Then, we examined the effects of Zn-induced MT4 overexpression and MT4 silencing on embryonic primary hepatocytes from breeder hens fed a normal Zn diet subjected to a tert-butyl hydroperoxide (BHP) oxidative stress challenge during incubation. In vivo, the avian embryos from hens fed the Zn-deficient and Znadequate diets were used to determine the protective roles of Zn-induced MT4 expression on the function of mitochondria exposed to oxidative stress induced by in ovo BHP injection. Results: An in vitro study revealed that Zn-induced MT4 expression reduced reactive oxygen species accumulation in primary hepatocytes. MT4 silencing exacerbated BHP-mediated mitochondrial dysfunction whereas Zn-inducible MT4 overexpression mitigated it. Another in vivo study disclosed that maternal Zn-induced MT4 expression protected mitochondrial function in chick embryo hepatocytes against oxidative stress by inhibiting the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha)/peroxisome proliferators-activated receptor-gamma (PPAR-gamma) pathway. Conclusion: This study underscores the potential protective roles of Zn-induced MT4 expression via the downregulation of the PGC-1 alpha/ PPAR-gamma pathway on mitochondrial function stimulated by the stress challenge in the primary hepatocytes in an avian embryo model. Our findings suggested that Zn-induced MT4 expression could provide a new therapeutic target and preventive strategy for repairing mitochondrial dysfunction in disease.

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