mTOR regulates PRMT1 expression and mitochondrial mass through STAT1 phosphorylation in hepatic cell,Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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mTOR regulates PRMT1 expression and mitochondrial mass through STAT1 phosphorylation in hepatic cell
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research ( IF 4.6 ) Pub Date : 2021-03-16 , DOI: 10.1016/j.bbamcr.2021.119017
Xiaozhen Zhang ₁ , Li Li ₁ , Yuwen Li ₁ , Zhi Li ₁ , Weiqi Zhai ₁ , Qingzhu Sun ₂ , Xiaojun Yang ₁ , Michael Roth ₃ , Shemin Lu ₄

Affiliation

Background

Fasting changes mitochondrial function, and mTOR acts as a major regulator of mitochondrial energy production ensuring the survival under reduced supply of nutrition. This study assessed the role of protein arginine methyltransferase 1 (PRMT1), which regulates mitochondrial function, in the context of fasting.

Methods

The effect of fasting on mTOR signaling and mTOR-regulated mitochondrial mass was assessed in LO2 cells (in vitro) and C57BL/6J mice (in vivo). Biochemical parameters of fasting were determined in blood samples of mice. PRMT1 expression was investigated by transfecting LO2 cells with an expression vector. Gene expression was determined by real-time quantitative PCR, protein interaction by chromatin immunoprecipitation, protein expression by Western blotting and immunofluorescence microscopy, and the mitochondrial mass by MitoTracker staining.

Results

After 48 h of fasting, mTOR and PRMT1 expression, as well as mitochondrial mass, were significantly reduced in LO2 cells, and in liver tissue sections. Fasting downregulated the expression of miR-21 and upregulated the expression of its target phosphatase and tensin homolog (PTEN), which was responsible for reduced mTOR expression. Inhibition of mTOR reduced phosphorylation of STAT1, and thereby PRMT1 expression in LO2 cells. Low PRMT1 down-regulated the expression of peroxisome proliferator-activated receptor (PPAR)-γ and thereby decreased mitochondrial mass. Supplementation of insulin contracted the effect of fasting on all mentioned parameters.

Conclusions

Fasting downregulates miR-21 and increases its target PTEN, thereby inhibiting mTOR signaling, p-STAT1, PRMT1, and mitochondrial mass. These findings highlight the role of mTOR and PRMT1 in the regulation of cellular energy availability.

中文翻译：

mTOR通过肝细胞中的STAT1磷酸化调节PRMT1表达和线粒体质量

背景

禁食会改变线粒体功能，mTOR 作为线粒体能量产生的主要调节器，确保在营养供应减少的情况下存活。本研究评估了蛋白质精氨酸甲基转移酶 1 (PRMT1) 在禁食情况下调节线粒体功能的作用。

方法

在 LO2 细胞（体外）和 C57BL/6J 小鼠（体内）中评估了禁食对 mTOR 信号传导和 mTOR 调节的线粒体质量的影响。在小鼠的血样中测定禁食的生化参数。通过用表达载体转染 LO2 细胞来研究 PRMT1 表达。基因表达通过实时定量 PCR、染色质免疫沉淀的蛋白质相互作用、蛋白质印迹和免疫荧光显微镜的蛋白质表达以及 MitoTracker 染色的线粒体质量确定。

结果

禁食 48 小时后，LO2 细胞和肝组织切片中的 mTOR 和 PRMT1 表达以及线粒体质量显着降低。禁食会下调 miR-21 的表达，并上调其靶标磷酸酶和张力蛋白同源物 (PTEN) 的表达，这是导致 mTOR 表达降低的原因。抑制 mTOR 会降低 STAT1 的磷酸化，从而降低 LO2 细胞中 PRMT1 的表达。低 PRMT1 下调过氧化物酶体增殖物激活受体 (PPAR)-γ 的表达，从而减少线粒体质量。胰岛素的补充收缩了禁食对所有提到的参数的影响。