抑制线粒体脂肪酸β-氧化激活mTORC1通路和斑马鱼猛禽通过Gcn5依赖性乙酰化的蛋白质合成。

The Journal of Biological Chemistry Pub Date : 2023-10-01 Epub Date: 2023-09-03 DOI:10.1016/j.jbc.2023.105220
Wen-Hao Zhou, Yuan Luo, Rui-Xin Li, Pascal Degrace, Tony Jourdan, Fang Qiao, Li-Qiao Chen, Mei-Ling Zhang, Zhen-Yu Du
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引用次数: 0

摘要

线粒体脂肪酸氧化的药理学抑制(FAO)已在临床上用于通过重塑细胞代谢来缓解某些代谢疾病。然而,线粒体FAO抑制也导致雷帕霉素复合物1(mTORC1)激活相关蛋白合成和组织肥大的机制靶点,但其机制尚不清楚。在这里,通过使用线粒体FAO抑制剂(mildronate或etomoxir)或敲除肉碱棕榈酰转移酶-1,我们发现线粒体FAO抑制通过一般控制的不可抑制的5-依赖性猛禽乙酰化激活mTORC1途径。线粒体FAO抑制显著促进葡萄糖分解代谢并增加细胞内乙酰辅酶A水平。为了响应细胞内乙酰辅酶A的增加,乙酰转移酶通过直接相互作用催化Raptor乙酰化,一般控制不可抑制5激活mTORC1。进一步的研究还筛选了猛禽脱乙酰酶组蛋白脱乙酰酶II类,并确定组蛋白脱酰酶7是猛禽的潜在调节因子。这些结果为线粒体FAO抑制后mTORC1的激活提供了可能的机制解释,也揭示了营养代谢重塑通过影响乙酰辅酶a的产生在调节蛋白质乙酰化中的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Inhibition of mitochondrial fatty acid β-oxidation activates mTORC1 pathway and protein synthesis via Gcn5-dependent acetylation of Raptor in zebrafish.

Inhibition of mitochondrial fatty acid β-oxidation activates mTORC1 pathway and protein synthesis via Gcn5-dependent acetylation of Raptor in zebrafish.

Inhibition of mitochondrial fatty acid β-oxidation activates mTORC1 pathway and protein synthesis via Gcn5-dependent acetylation of Raptor in zebrafish.

Inhibition of mitochondrial fatty acid β-oxidation activates mTORC1 pathway and protein synthesis via Gcn5-dependent acetylation of Raptor in zebrafish.

Pharmacological inhibition of mitochondrial fatty acid oxidation (FAO) has been clinically used to alleviate certain metabolic diseases by remodeling cellular metabolism. However, mitochondrial FAO inhibition also leads to mechanistic target of rapamycin complex 1 (mTORC1) activation-related protein synthesis and tissue hypertrophy, but the mechanism remains unclear. Here, by using a mitochondrial FAO inhibitor (mildronate or etomoxir) or knocking out carnitine palmitoyltransferase-1, we revealed that mitochondrial FAO inhibition activated the mTORC1 pathway through general control nondepressible 5-dependent Raptor acetylation. Mitochondrial FAO inhibition significantly promoted glucose catabolism and increased intracellular acetyl-CoA levels. In response to the increased intracellular acetyl-CoA, acetyltransferase general control nondepressible 5 activated mTORC1 by catalyzing Raptor acetylation through direct interaction. Further investigation also screened Raptor deacetylase histone deacetylase class II and identified histone deacetylase 7 as a potential regulator of Raptor. These results provide a possible mechanistic explanation for the mTORC1 activation after mitochondrial FAO inhibition and also bring light to reveal the roles of nutrient metabolic remodeling in regulating protein acetylation by affecting acetyl-CoA production.

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