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SHR Neuro Cancer Cardio Lipid Metab Microb
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; Frezza, C.
Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism.
Elife. 2021; 10:
Doi: 10.7554/eLife.72593
[OPEN ACCESS]
Web of Science
PubMed
FullText
FullText_MUG
- Co-authors Med Uni Graz
- Rodriguez Blanco Giovanny
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Activating Transcription Factor 4 - metabolism
- Amino Acids - metabolism
- Animals - administration & dosage
- Cells, Cultured - administration & dosage
- Citric Acid Cycle - genetics, physiology
- Fumarate Hydratase - metabolism
- Kidney - metabolism
- Metabolome - administration & dosage
- Mice - administration & dosage
- Oxidation-Reduction - administration & dosage
- RNA Interference - administration & dosage
- Succinate Dehydrogenase - metabolism
- Find related publications in this database (Keywords)
- TCA cycle
- mitochondria
- metabolism
- metabolomics
- Mouse