MRC Cancer Unit, University of Cambridge, Hutchison MRC Research Centre, Cambridge Biomedical Campus, Cambridge, United Kingdom.
MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.
Elife. 2021 Dec 23;10:e72593. doi: 10.7554/eLife.72593.
The Tricarboxylic Acid (TCA) Cycle is arguably the most critical metabolic cycle in physiology and exists as an essential interface coordinating cellular metabolism, bioenergetics, and redox homeostasis. Despite decades of research, a comprehensive investigation into the consequences of TCA cycle dysfunction remains elusive. Here, we targeted two TCA cycle enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDH), and combined metabolomics, transcriptomics, and proteomics analyses to fully appraise the consequences of TCA cycle inhibition (TCAi) in murine kidney epithelial cells. Our comparative approach shows that TCAi elicits a convergent rewiring of redox and amino acid metabolism dependent on the activation of ATF4 and the integrated stress response (ISR). Furthermore, we also uncover a divergent metabolic response, whereby acute FHi, but not SDHi, can maintain asparagine levels via reductive carboxylation and maintenance of cytosolic aspartate synthesis. Our work highlights an important interplay between the TCA cycle, redox biology, and amino acid homeostasis.
三羧酸（TCA）循环可以说是生理学中最重要的代谢循环，它作为一个重要的界面，协调细胞代谢、生物能量学和氧化还原平衡。尽管经过了几十年的研究，对 TCA 循环功能障碍后果的全面研究仍然难以捉摸。在这里，我们针对两种 TCA 循环酶，延胡索酸水合酶（FH）和琥珀酸脱氢酶（SDH），并结合代谢组学、转录组学和蛋白质组学分析，全面评估了 TCA 循环抑制（TCAi）在小鼠肾脏上皮细胞中的后果。我们的比较方法表明，TCAi 引发了依赖于 ATF4 和综合应激反应（ISR）激活的氧化还原和氨基酸代谢的收敛重布线。此外，我们还发现了一种不同的代谢反应，即急性 FH i，但不是 SDHi，可以通过还原羧化作用和维持细胞溶质天冬氨酸合成来维持天冬酰胺水平。我们的工作强调了 TCA 循环、氧化还原生物学和氨基酸动态平衡之间的重要相互作用。
