Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism.
Blanco, Giovanny Rodriguez
Miljkovic, Jan Lj
von Kriegsheim, Alex
eLife Sciences Publications, Ltd
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Ryan, D. G., Yang, M., Prag, H., Blanco, G. R., Nikitopoulou, E., Segarra-Mondejar, M., Powell, C. A., et al. (2021). Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism.. Elife, 10 https://doi.org/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.
Research Article, Biochemistry and Chemical Biology, Cell Biology, TCA cycle, mitochondria, metabolism, metabolomics, Mouse
Medical Research Council (MC_UU_12022/6)
European Research Council (819920)
Medical Research Council (MC_UU_00015/4)
External DOI: https://doi.org/10.7554/eLife.72593
This record's URL: https://www.repository.cam.ac.uk/handle/1810/332541