Operation of a TCA cycle subnetwork in the mammalian nucleus

  • Nucleic acid and histone modifications critically depend on the tricarboxylic acid (TCA) cycle for substrates and cofactors. Although a few TCA cycle enzymes have been reported in the nucleus, the corresponding pathways are considered to operate in mitochondria. Here, we show that a part of the TCA cycle is operational also in the nucleus. Using 13C-tracer analysis, we identified activity of glutamine-to-fumarate, citrate-to-succinate, and glutamine-to-aspartate routes in the nuclei of HeLa cells. Proximity labeling mass spectrometry revealed a spatial vicinity of the involved enzymes with core nuclear proteins. We further show nuclear localization of aconitase 2 and 2-oxoglutarate dehydrogenase in mouse embryonic stem cells. Nuclear localization of the latter enzyme, which produces succinyl-CoA, changed from pluripotency to a differentiated state with accompanying changes in the nuclear protein succinylation. Together, our results demonstrate operation of an extended metabolic pathway in the nucleus, warranting a revision of the canonical view on metabolic compartmentalization.

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Author:Eleni KafkiaORCiDGND, Amparo Andres-PonsORCiD, Kerstin GanterORCiD, Markus SeilerORCiDGND, Tom S. SmithORCiD, Anna Andrejeva, Paula JouhtenORCiDGND, Filipa PereiraORCiD, Catarina FrancoORCiD, Anna Kuroshchenkova, Sergio LeoneORCiDGND, Ritwick SawarkarGND, Rebecca BostonORCiD, James ThaventhiranORCiD, Judith B. ZauggORCiDGND, Kathryn S. LilleyORCiD, Christophe LancrinORCiD, Martin BeckORCiDGND, Kiran Raosaheb PatilORCiDGND
Parent Title (English):Science advances
Publisher:American Association for the Advancement of Science
Place of publication:Washington, DC [u.a.]
Document Type:Article
Date of Publication (online):2022/08/31
Date of first Publication:2022/08/31
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2023/07/26
Issue:35, art. eabq5206
Article Number:eabq5206
Page Number:17
Institutes:Angeschlossene und kooperierende Institutionen / MPI für Biophysik
Fachübergreifende Einrichtungen / Buchmann Institut für Molekulare Lebenswissenschaften (BMLS)
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Licence (German):License LogoCreative Commons - Namensnennung 4.0