1. Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism.
- Author
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Ryan DG, Yang M, Prag HA, Blanco GR, Nikitopoulou E, Segarra-Mondejar M, Powell CA, Young T, Burger N, Miljkovic JL, Minczuk M, Murphy MP, von Kriegsheim A, and Frezza C
- Subjects
- Amino Acids metabolism, Animals, Cells, Cultured, Citric Acid Cycle genetics, Kidney metabolism, Metabolome, Mice, Oxidation-Reduction, RNA Interference, Activating Transcription Factor 4 metabolism, Citric Acid Cycle physiology, Fumarate Hydratase metabolism, Succinate Dehydrogenase metabolism
- 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., Competing Interests: DR, MY, HP, GB, EN, MS, CP, TY, NB, JM, MM, MM, Av, CF No competing interests declared, (© 2021, Ryan et al.)
- Published
- 2021
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