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dc.contributor.authorRyan, Dylan Gerard
dc.contributor.authorYang, Ming
dc.contributor.authorPrag, Hiran
dc.contributor.authorBlanco, Giovanny Rodriguez
dc.contributor.authorNikitopoulou, Efterpi
dc.contributor.authorSegarra-Mondejar, Marc
dc.contributor.authorPowell, Christopher A
dc.contributor.authorYoung, Tim
dc.contributor.authorBurger, Nils
dc.contributor.authorMiljkovic, Jan Lj
dc.contributor.authorMinczuk, Michal
dc.contributor.authorMurphy, Mike
dc.contributor.authorvon Kriegsheim, Alex
dc.contributor.authorFrezza, Christian
dc.date.accessioned2022-01-10T12:50:05Z
dc.date.available2022-01-10T12:50:05Z
dc.date.issued2021-12-23
dc.date.submitted2021-07-28
dc.identifier.issn2050-084X
dc.identifier.other72593
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/332541
dc.description.abstractThe 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.
dc.languageen
dc.publishereLife Sciences Publications, Ltd
dc.subjectResearch Article
dc.subjectBiochemistry and Chemical Biology
dc.subjectCell Biology
dc.subjectTCA cycle
dc.subjectmitochondria
dc.subjectmetabolism
dc.subjectmetabolomics
dc.subjectMouse
dc.titleDisruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism.
dc.typeArticle
dc.date.updated2022-01-10T12:50:04Z
prism.publicationNameElife
prism.volume10
dc.identifier.doi10.17863/CAM.79991
dcterms.dateAccepted2021-12-21
rioxxterms.versionofrecord10.7554/eLife.72593
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
datacite.contributor.supervisoreditor: Vander Heiden, Matthew G
datacite.contributor.supervisorsenior_editor: Barton, Matthias
dc.contributor.orcidRyan, Dylan Gerard [0000-0003-4553-9192]
dc.contributor.orcidPrag, Hiran [0000-0002-4753-8567]
dc.contributor.orcidPowell, Christopher A [0000-0001-7501-0586]
dc.contributor.orcidYoung, Tim [0000-0002-1831-3473]
dc.contributor.orcidMinczuk, Michal [0000-0001-8242-1420]
dc.contributor.orcidMurphy, Mike [0000-0003-1115-9618]
dc.contributor.orcidFrezza, Christian [0000-0002-3293-7397]
dc.identifier.eissn2050-084X
pubs.funder-project-idMedical Research Council (MC_UU_12022/6)
pubs.funder-project-idEuropean Research Council (819920)
pubs.funder-project-idMedical Research Council (MC_UU_00015/4)
cam.issuedOnline2021-12-23


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