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Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism.
Ryan, Dylan Gerard; Yang, Ming; Prag, Hiran A; Blanco, Giovanny Rodriguez; Nikitopoulou, Efterpi; Segarra-Mondejar, Marc; Powell, Christopher A; Young, Tim; Burger, Nils; Miljkovic, Jan Lj; Minczuk, Michal; Murphy, Michael P; von Kriegsheim, Alex; Frezza, Christian.
Afiliação
  • Ryan DG; MRC Cancer Unit, University of Cambridge, Hutchison MRC Research Centre, Cambridge Biomedical Campus, Cambridge, United Kingdom.
  • Yang M; MRC Cancer Unit, University of Cambridge, Hutchison MRC Research Centre, Cambridge Biomedical Campus, Cambridge, United Kingdom.
  • Prag HA; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.
  • Blanco GR; Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.
  • Nikitopoulou E; Edinburgh Cancer Research UK Centre, Institute of Genetics and Cancer, Edinburgh, United Kingdom.
  • Segarra-Mondejar M; MRC Cancer Unit, University of Cambridge, Hutchison MRC Research Centre, Cambridge Biomedical Campus, Cambridge, United Kingdom.
  • Powell CA; MRC Cancer Unit, University of Cambridge, Hutchison MRC Research Centre, Cambridge Biomedical Campus, Cambridge, United Kingdom.
  • Young T; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.
  • Burger N; MRC Cancer Unit, University of Cambridge, Hutchison MRC Research Centre, Cambridge Biomedical Campus, Cambridge, United Kingdom.
  • Miljkovic JL; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.
  • Minczuk M; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.
  • Murphy MP; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.
  • von Kriegsheim A; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.
  • Frezza C; Edinburgh Cancer Research UK Centre, Institute of Genetics and Cancer, Edinburgh, United Kingdom.
Elife ; 102021 12 23.
Article em En | MEDLINE | ID: mdl-34939929
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Succinato Desidrogenase / Ciclo do Ácido Cítrico / Fator 4 Ativador da Transcrição / Fumarato Hidratase Limite: Animals Idioma: En Revista: Elife Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Reino Unido

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Succinato Desidrogenase / Ciclo do Ácido Cítrico / Fator 4 Ativador da Transcrição / Fumarato Hidratase Limite: Animals Idioma: En Revista: Elife Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Reino Unido