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<p>Mitochondria remain at the core of cell metabolism, whereas the nucleus integrates cellular and environmental signals to activate genes. However, the mechanisms that directly link cellular metabolism to gene regulation are not well understood. Here we show, a metabolic pathway in the nucleus controls acetylation of histones by nuclear localization of mitochondrial enzymes aconitase (ACO2) and isocitrate dehydrogenase (IDH2). Metabolic tracing studies show that IDH2 and ACO2 catalyze reductive carboxylation of α-ketoglutarate to rapidly synthesize citrate to increase nuclear acetyl-CoA pool. Genetic and proteomic analyses reveal nuclear IDH2 and ACO2 form a complex with KAT2A/GCN5 for acetylation of histones to increase chromatin accessibility and activation of proliferative genes. Robust nuclear expressions of ACO2 and IDH2 drive aggressive tumors indicating the tumorigenic potential of IDH2-ACO2-KAT2A axis. Altogether, our work reveals a paradigm coupling a nuclear metabolic pathway with histone acetylation to control of gene expression that accentuates hyperproliferative phenotype in tumors.</p>

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Nuclear-specific reductive carboxylation of alpha-ketoglutarate fuels histone acetylation to induce chromatin accessibility and gene activation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月1日

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  • Abhisha Sawant Dessai,
  • Nadya A. Elhalawany,
  • Tao Dai,
  • Justine J. Jacobi,
  • Christian Prechtl,
  • Alphonse N. Dimeck,
  • Sierra R. Morton,
  • Mark D. Long,
  • Prashant K. Singh,
  • Nagireddy Putluri,
  • Mariana Lopes,
  • Song Liu,
  • Dominic J. Smiraglia,
  • Katerina V. Gurova,
  • Peder J. Lund,
  • Leah A. Gates,
  • Sung Yun Jung,
  • Subhamoy Dasgupta

摘要

Mitochondria remain at the core of cell metabolism, whereas the nucleus integrates cellular and environmental signals to activate genes. However, the mechanisms that directly link cellular metabolism to gene regulation are not well understood. Here we show, a metabolic pathway in the nucleus controls acetylation of histones by nuclear localization of mitochondrial enzymes aconitase (ACO2) and isocitrate dehydrogenase (IDH2). Metabolic tracing studies show that IDH2 and ACO2 catalyze reductive carboxylation of α-ketoglutarate to rapidly synthesize citrate to increase nuclear acetyl-CoA pool. Genetic and proteomic analyses reveal nuclear IDH2 and ACO2 form a complex with KAT2A/GCN5 for acetylation of histones to increase chromatin accessibility and activation of proliferative genes. Robust nuclear expressions of ACO2 and IDH2 drive aggressive tumors indicating the tumorigenic potential of IDH2-ACO2-KAT2A axis. Altogether, our work reveals a paradigm coupling a nuclear metabolic pathway with histone acetylation to control of gene expression that accentuates hyperproliferative phenotype in tumors.