摘要
The scope and variety of the metabolic intermediates from the mitochondrial tricarboxylic acid(TCA)cycle that are engaged in epigenetic regulation of the chromatin function in the nucleus raise an outstanding question about how timely and precise supply/consumption of these metabolites is achieved in the nucleus.We report here the identification of a nonclassical TCA cycle in the nucleus(nTCA cycle).We found that all the TCA cycle-associated enzymes including citrate synthase(CS),aconitase 2(ACO2),isocitrate dehydrogenase 3(IDH3),oxoglutarate dehydrogenase(OGDH),succinyl-CoA synthetase(SCS),fumarate hydratase(FH),and malate dehydrogenase 2(MDH2),except for succinate dehydrogenase(SDH),a component of electron transport chain for generating ATP,exist in the nucleus.We showed that these nuclear enzymes catalyze an incomplete TCA cycle similar to that found in cyanobacteria.We propose that the nTCA cycle is implemented mainly to generate/consume metabolic intermediates,not for energy production.We demonstrated that the nTCA cycle is intrinsically linked to chromatin dynamics and transcription regulation.Together,our study uncovers the existence of a nonclassical TCA cycle in the nucleus that links the metabolic pathway to epigenetic regulation.
基金
This work was supported by a grant(2016YFC1302304 to Y.S.)from the Ministry of Science and Technology of China
a grant(Z200020 to L.S.)from the Natural Science Foundation of Beijing
a grant(QNBJ2020-2 to L.S.)from National Program for Support of Top-notch Young Professionals
grants(81530073 and 81730079 to Y.S.,31571340 and 81874158 to L.S.,81972659 to W.S.)from the National Natural Science Foundation of China.
