PDF(Pubmed)
Abstract：
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.
摘要：
线粒体脂肪酸氧化（FAO）的药理学抑制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mTORC1活化相关蛋白合成和组织肥大，但机制尚不清楚。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Gcn5依赖性Raptor乙酰化激活mTORC1途径。线粒体FAO抑制显着促进葡萄糖分解代谢并增加细胞内乙酰辅酶A水平。为了响应增加的细胞内乙酰辅酶A，乙酰转移酶Gcn5通过直接相互作用催化Raptor乙酰化作用激活mTORC1。进一步的研究还筛选了Raptor脱乙酰酶HDACII类，并确定HDAC7是Raptor的潜在调节剂。这些结果为线粒体FAO抑制后的mTORC1激活提供了可能的机制解释，也揭示了营养代谢重塑在通过影响乙酰辅酶A产生调节蛋白质乙酰化中的作用。
