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Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Yang, Ming 
Prag, Hiran A 
Blanco, Giovanny Rodriguez 
Nikitopoulou, Efterpi 

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.

Description

Keywords

TCA cycle, biochemistry, cell biology, chemical biology, metabolism, metabolomics, mitochondria, mouse, Activating Transcription Factor 4, Amino Acids, Animals, Cells, Cultured, Citric Acid Cycle, Fumarate Hydratase, Kidney, Metabolome, Mice, Oxidation-Reduction, RNA Interference, Succinate Dehydrogenase

Journal Title

Elife

Conference Name

Journal ISSN

2050-084X
2050-084X

Volume Title

10

Publisher

eLife Sciences Publications, Ltd
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)
Medical Research Council (MC_UU_00015/7)
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