Sirt3-Sod2-mROS 介导的锰在淡水硬骨鱼中引发肝线粒体功能障碍和脂毒性,Environmental Science & Technology

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Sirt3-Sod2-mROS 介导的锰在淡水硬骨鱼中引发肝线粒体功能障碍和脂毒性
Environmental Science & Technology ( IF 10.8 ) Pub Date : 2022-06-02 , DOI: 10.1021/acs.est.2c00585
Tao Zhao ₁ , Wu-Hong Lv ₁ , Christer Hogstrand ₂ , Dian-Guang Zhang ₁ , Yi-Chuang Xu ₁ , Yi-Huan Xu ₁ , Zhi Luo _{1,

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Affiliation

接触过量的锰 (Mn) 对人类和动物都是有毒的。然而，过量锰对脊椎动物的毒性作用和机制却被高度忽视。在本研究中，膳食锰超载显着增加肝脏脂质和锰含量，降低超氧化物歧化酶 2（Sod2）活性，增加 Sod2 乙酰化水平，并诱导线粒体功能障碍；Mn 通过 Mtf1/sirtuin 3 (Sirt3) 介导的 Sod2 在 K55 和 K70 位点的乙酰化诱导线粒体功能障碍。同时，线粒体氧化应激参与了锰诱导的脂毒性。从机制上讲，Mn 诱导的脂毒性是通过氧化应激诱导的 Hsf1 核易位及其与过氧化物酶体增殖物激活受体 g区域的 DNA 结合能力。pparg ) 启动子，进而诱导脂肪生成相关靶基因的转录。我们的研究首次证明，通过线粒体氧化应激依赖性 Hsf1/Pparg 通路和 Mtf1/ sirt3介导的 Sod2 乙酰化，Mn 诱导的肝脂毒性参与了线粒体功能障碍。考虑到脂质代谢和脂毒性被广泛用作污染物环境评估的生物标志物，我们的研究为水环境中锰毒理学和环境评估提供了创新和重要的见解。

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Sirt3-Sod2-mROS-Mediated Manganese Triggered Hepatic Mitochondrial Dysfunction and Lipotoxicity in a Freshwater Teleost

Exposure to excessive manganese (Mn) is toxic to humans and animals. However, the toxic effects and mechanisms of excessive Mn influencing the vertebrates have been highly overlooked. In the present study, dietary Mn overload significantly increased hepatic lipid and Mn contents, decreased superoxide dismutase 2 (Sod2) activity, increased the Sod2 acetylation level, and induced mitochondrial dysfunction; Mn induced mitochondrial dysfunction through Mtf1/sirtuin 3 (Sirt3)-mediated acetylation of Sod2 at the sites K55 and K70. Meanwhile, mitochondrial oxidative stress was involved in Mn-induced lipotoxicity. Mechanistically, Mn-induced lipotoxicity was via oxidative stress-induced Hsf1 nucleus translocation and its DNA binding capacity to the regions of a peroxisome proliferator-activated receptor g (pparg) promoter, which in turn induced the transcription of lipogenic-related target genes. For the first time, our study demonstrated that Mn-induced hepatic lipotoxicity via a mitochondrial oxidative stress-dependent Hsf1/Pparg pathway and Mtf1/sirt3-mediated Sod2 acetylation participated in mitochondrial dysfunction. Considering that lipid metabolism and lipotoxicity are widely used as the biomarkers for environmental assessments of pollutants, our study provided innovative and important insights into Mn toxicological and environmental evaluation in aquatic environments.

更新日期：2022-06-02

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