MRC Cancer Unit, University of Cambridge, Hutchison MRC Research Centre, Cambridge Biomedical Campus, Cambridge, United Kingdom
Ming Yang
MRC Cancer Unit, University of Cambridge, Hutchison MRC Research Centre, Cambridge Biomedical Campus, Cambridge, United Kingdom
Hiran A Prag
MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom
Giovanny Rodriguez Blanco
Edinburgh Cancer Research UK Centre, Institute of Genetics and Cancer, Edinburgh, United Kingdom
Efterpi Nikitopoulou
MRC Cancer Unit, University of Cambridge, Hutchison MRC Research Centre, Cambridge Biomedical Campus, Cambridge, United Kingdom
Marc Segarra-Mondejar
MRC Cancer Unit, University of Cambridge, Hutchison MRC Research Centre, Cambridge Biomedical Campus, Cambridge, United Kingdom
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.
