2022

Kafkia, Eleni; Andres-Pons, Amparo; Ganter, Kerstin; Seiler, Markus; Smith, Tom S.; Andrejeva, Anna; Jouhten, Paula; Pereira, Filipa; Franco, Catarina; Kuroshchenkova, Anna; Leone, Sergio; Sawarkar, Ritwick; Boston, Rebecca; Thaventhiran, James; Zaugg, Judith B.; Lilley, Kathryn S.; Lancrin, Christophe; Beck, Martin; Patil, Kiran Raosaheb

<p>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.</p>