Sirt3-Sod2-mROS-Mediated Manganese Triggered Hepatic Mitochondrial Dysfunction and Lipotoxicity in a Freshwater Teleost.
Sirt3-Sod2-mROS-Mediated Manganese Triggered Hepatic Mitochondrial Dysfunction and Lipotoxicity in a Freshwater Teleost.
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Sirt 3-Sod 2-mROS介导的锰引发淡水硬骨鱼肝线粒体功能障碍和脂毒性
DOI：
10.1021/acs.est.2c00585
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发表时间：
2022-06
影响因子：
11.4
通讯作者：
Tao Zhao;Wu-Hong Lv;C. Hogstrand;Dian-Guang Zhang;Yi-Chuang Xu;Yi-Huan Xu;Zhi Luo
中科院分区：
文献类型：
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作者：
Tao Zhao;Wu-Hong Lv;C. Hogstrand;Dian-Guang Zhang;Yi-Chuang Xu;Yi-Huan Xu;Zhi Luo
暴露于过量的锰（Mn）对人类和动物是有毒的。然而，过量锰对脊椎动物的毒性作用及其机制却被严重忽视。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（SOD 2）的活性，增加SOD 2乙酰化水平，并诱导线粒体功能障碍;锰诱导线粒体功能障碍，通过Mtf 1/sirtuin 3（Sirt 3）介导的SOD 2的乙酰化位点K55和K70。同时，线粒体氧化应激参与锰诱导的脂毒性。从机制上讲，锰诱导的脂毒性是通过氧化应激诱导的Hsf 1核转位及其与过氧化物酶体增殖物激活受体g（pparg）启动子区域的DNA结合能力，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，锰诱导的肝脂毒性通过线粒体氧化应激依赖的Hsf 1/Pparg途径和Mtf 1/sirt 3介导的Sod 2乙酰化参与线粒体功能障碍。考虑到脂代谢和脂毒性被广泛用作污染物环境评价的生物标志物，我们的研究为水环境中Mn的毒理学和环境评价提供了创新和重要的见解。
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.