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  3. Malic enzyme 2 connects the Krebs cycle intermediate fumarate to mitochondrial biogenesis

Malic enzyme 2 connects the Krebs cycle intermediate fumarate to mitochondrial biogenesis

  • Cell Metab. 2021 May 4;33(5):1027-1041.e8. doi: 10.1016/j.cmet.2021.03.003.
Yi-Ping Wang 1,  Azeem Sharda 2,  Shuang-Nian Xu 3,  Nick van Gastel 2,  Cheuk Him Man 2,  Una Choi 4,  Wei Zhong Leong 2,  Xi Li 3,  David T Scadden 5
Affiliations

Affiliations

  • 1 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, Key Laboratory of Breast Cancer in Shanghai, Cancer Institute, Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai 20032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 20032, China.
  • 2 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 3 Department of Hematology, Southwest Hospital, Army Medical University, Chongqing 400038, China.
  • 4 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
  • 5 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: david_scadden@harvard.edu.
PMID: 33770508 DOI: 10.1016/j.cmet.2021.03.003
Abstract

Mitochondria have an independent genome (mtDNA) and protein synthesis machinery that coordinately activate for mitochondrial generation. Here, we report that the Krebs cycle intermediate fumarate links metabolism to mitobiogenesis through binding to malic Enzyme 2 (ME2). Mechanistically, fumarate binds ME2 with two complementary consequences. First, promoting the formation of ME2 dimers, which activate deoxyuridine 5'-triphosphate nucleotidohydrolase (DUT). DUT fosters thymidine generation and an increase of mtDNA. Second, fumarate-induced ME2 dimers abrogate ME2 monomer binding to mitochondrial ribosome protein L45, freeing it for mitoribosome assembly and mtDNA-encoded protein production. Methylation of the ME2-fumarate binding site by protein arginine methyltransferase-1 inhibits fumarate signaling to constrain mitobiogenesis. Notably, acute myeloid leukemia is highly dependent on mitochondrial function and is sensitive to targeting of the fumarate-ME2 axis. Therefore, mitobiogenesis can be manipulated in normal and malignant cells through ME2, an unanticipated governor of mitochondrial biomass production that senses nutrient availability through fumarate.

Keywords

acute myeloid leukemia; arginine methylation; deoxyuridine 5′-triphosphate nucleotidohydrolase; fumarate; malic enzyme 2; mitobiogenesis; mitochondrial ribosome; mitochondrial ribosome protein L45; protein arginine methyltransferase 1.

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  • HY-124062
    99.54%, dUTPase/DPD抑制剂
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