Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
Waisman Center, University of Wisconsin-Madison, Madison, WI, USA.
Commun Biol. 2023 Sep 9;6(1):926. doi: 10.1038/s42003-023-05311-1.
Cytosolic citrate is imported from the mitochondria by SLC25A1, and from the extracellular milieu by SLC13A5. In the cytosol, citrate is used by ACLY to generate acetyl-CoA, which can then be exported to the endoplasmic reticulum (ER) by SLC33A1. Here, we report the generation of mice with systemic overexpression (sTg) of SLC25A1 or SLC13A5. Both animals displayed increased cytosolic levels of citrate and acetyl-CoA; however, SLC13A5 sTg mice developed a progeria-like phenotype with premature death, while SLC25A1 sTg mice did not. Analysis of the metabolic profile revealed widespread differences. Furthermore, SLC13A5 sTg mice displayed increased engagement of the ER acetylation machinery through SLC33A1, while SLC25A1 sTg mice did not. In conclusion, our findings point to different biological responses to SLC13A5- or SLC25A1-mediated import of citrate and suggest that the directionality of the citrate/acetyl-CoA pathway can transduce different signals.
细胞质中的柠檬酸由 SLC25A1 从线粒体中输入，由 SLC13A5 从细胞外环境中输入。在细胞质中，柠檬酸被 ACLY 用于生成乙酰辅酶 A，然后乙酰辅酶 A 可以通过 SLC33A1 输出到内质网 (ER)。在这里，我们报告了 SLC25A1 或 SLC13A5 全身过表达 (sTg) 的小鼠的产生。两种动物的细胞质中柠檬酸和乙酰辅酶 A 的水平都增加了；然而，SLC13A5 sTg 小鼠表现出类似于早衰的表型，导致过早死亡，而 SLC25A1 sTg 小鼠则没有。代谢谱分析显示存在广泛的差异。此外，SLC13A5 sTg 小鼠通过 SLC33A1 显示出 ER 乙酰化机制的增加参与，而 SLC25A1 sTg 小鼠则没有。总之，我们的研究结果表明，SLC13A5 或 SLC25A1 介导的柠檬酸输入会引起不同的生物学反应，并表明柠檬酸/乙酰辅酶 A 途径的方向性可以传递不同的信号。
