Ryan, Dylan Gerard, Yang, Ming, Prag, Hiran A., Blanco, Giovanny Rodriguez, Nikitopoulou, Efterpi, Segarra-Mondejar, Marc, Powell, Christopher A., Young, Tim, Burger, Nils ORCID: 0000-0003-3227-8894, Miljkovic, Jan Lj, Minczuk, Michal ORCID: 0000-0001-8242-1420, Murphy, Michael P., von Kriegsheim, Alex and Frezza, Christian (2021). Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism. eLife, 10. CAMBRIDGE: eLIFE SCIENCES PUBL LTD. ISSN 2050-084X

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Ryan, Dylan GerardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yang, MingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prag, Hiran A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blanco, Giovanny RodriguezUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nikitopoulou, EfterpiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Segarra-Mondejar, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Powell, Christopher A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Young, TimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burger, NilsUNSPECIFIEDorcid.org/0000-0003-3227-8894UNSPECIFIED
Miljkovic, Jan LjUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Minczuk, MichalUNSPECIFIEDorcid.org/0000-0001-8242-1420UNSPECIFIED
Murphy, Michael P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Kriegsheim, AlexUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frezza, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-576090
DOI: 10.7554/eLife.72593; 10.7554/eLife.72593.sa0; 10.7554/eLife.72593.sa1; 10.7554/eLife.72593.sa2
Journal or Publication Title: eLife
Volume: 10
Date: 2021
Publisher: eLIFE SCIENCES PUBL LTD
Place of Publication: CAMBRIDGE
ISSN: 2050-084X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
FUMARATE-HYDRATASE; CITRIC-ACID; STRESS-RESPONSE; MITOCHONDRIAL; PROLINE; CELLS; CHAIN; CARBOXYLATION; GENERATION; TISSUEMultiple languages
BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/57609

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