Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism.
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Authors
Yang, Ming
Prag, Hiran A
Blanco, Giovanny Rodriguez
Nikitopoulou, Efterpi
Segarra-Mondejar, Marc
Burger, Nils
Miljkovic, Jan Lj
Minczuk, Michal
von Kriegsheim, Alex
Publication Date
2021-12-23Journal Title
Elife
ISSN
2050-084X
Publisher
eLife Sciences Publications, Ltd
Volume
10
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Ryan, D. G., Yang, M., Prag, H. A., 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
Abstract
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.
Keywords
Mitochondria, Metabolism, Biochemistry, Cell biology, Mouse, TCA cycle, Metabolomics, Chemical Biology
Sponsorship
Medical Research Council (MC_UU_12022/6)
European Research Council (819920)
Medical Research Council (MC_UU_00015/4)
Medical Research Council (MC_UU_00015/3)
Identifiers
34939929, PMC8735863
External DOI: https://doi.org/10.7554/eLife.72593
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333306
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