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Cited by 97Epigenetics and DNA MethylationCancer, Hypoxia, and MetabolismGenomics and Chromatin Dynamics

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

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Liu, Xujun, Si, Wenzhe, He, Lin, Yang, Jianguo, Peng, Yani, Ren, Jie, Liu, Xiaoping, Jin, Tong +15 more·2021·Signal Transduction and Targeted Therapy
DOI 10.1038/s41392-021-00774-2PMC PMC8563883
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Abstract

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.

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Cited by

Sorted by citations

Authors
Liu, X., Si, W., He, L., Yang, J., Peng, Y., Ren, J., Liu, X., Jin, T., Yu, H., Zhang, Z., Cheng, X., Zhang, W., Xia, L., Huang, Y., Wang, Y., Liu, S., Shan, L., Zhang, Y., Yang, X., Li, H., Liang, J., Sun, L., & Shang, Y.
Affiliations
  • Peking University (CN)
  • Hangzhou Normal University (CN)
  • Capital Medical University (CN)
  • Peking University First Hospital (CN)
Corresponding author
  • Sun, Luyang
  • Shang, Yongfeng
ORCID
Venue
Signal Transduction and Targeted Therapy
Publisher
Springer Science and Business Media LLC
Published
2021-11-03
Volume
6
Issue
1
Pages
375-375
ISSN
2059-3635 (ISSN-L)
DOI
10.1038/s41392-021-00774-2
PMC
PMC8563883
OpenAlex
W3210142854
Cited by
97
References
12
Citations by year
2026: 18 · 2025: 27 · 2024: 18 · 2023: 19 · 2022: 15
FWCI
4.08
Type
journal article
Language
en
Open access
Licence
Locations
  • Signal Transduction and Targeted Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (81730079, 81530073, 81972659, 31571340, 81874158)
  • Natural Science Foundation of Beijing Municipality (Z200020)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
mitochondrial metabolites, epigenetic regulation, chromatin dynamics, transcriptional regulation, citrate synthase, aconitase 2, 2-oxoglutarate dehydrogenase, succinyl-CoA synthetase, fumarate hydratase, MDH2, succinate dehydrogenase, nuclear enzymes
MeSH terms
Aconitate Hydratase, Cyanobacteria, Cell Nucleus, Chromatin, Citrate (si)-Synthase, Citric Acid Cycle, Energy Metabolism, Fumarate Hydratase, Humans, Isocitrate Dehydrogenase, Ketoglutarate Dehydrogenase Complex, Malate Dehydrogenase, Transcription, Genetic, Tricarboxylic Acids, Epigenesis, Genetic

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