The existence of a nonclassical TCA cycle in the nucleus that wires the metabolic-epigenetic circuitry

• DOI: 10.1038/s41392-021-00774-2
• Publication Date: 2021-11-03T01:03:06Z
• Authors: Xujun Liu; Wenzhe Si; Lin He; Jianguo Yang; Yani Peng; Jie Ren; Xiaoping Liu; Tong Jin; Huajing Yu; Zihan Zhang; Xiao Cheng; Wenting Zhang; Lu Xia; Yunchao Huang; Yue Wang; Shumeng Liu; Lin Shan; Yu Zhang; Xiaohan Yang; Haixia Li; Jing Liang; Luyang Sun; Yongfeng Shang
• Keywords: Aconitate Hydratase; Cell Nucleus; 0303 health sciences; Transcription, Genetic; QH301-705.5; Citric Acid Cycle; R; Tricarboxylic Acids; Citrate (si)-Synthase; Cyanobacteria; Article; Chromatin; Isocitrate Dehydrogenase; Epigenesis, Genetic; Fumarate Hydratase; 03 medical and health sciences; Malate Dehydrogenase; Medicine; Humans; Ketoglutarate Dehydrogenase Complex; Biology (General); Energy Metabolism

AbstractThe 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.