2. Academic Validation
  3. AKT1 phosphorylation of cytoplasmic ME2 induces a metabolic switch to glycolysis for tumorigenesis

AKT1 phosphorylation of cytoplasmic ME2 induces a metabolic switch to glycolysis for tumorigenesis

  • Nat Commun. 2024 Jan 23;15(1):686. doi: 10.1038/s41467-024-44772-8.
Taiqi Chen # 1 2 3,  Siyi Xie # 2 3,  Jie Cheng 2 3,  Qiao Zhao 4,  Hong Wu 5 6,  Peng Jiang 7 8 9,  Wenjing Du 10
Affiliations

Affiliations

  • 1 Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), South Medical University, Guangzhou, 510080, China.
  • 2 State Key Laboratory of Molecular Oncology, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
  • 3 Tsinghua-Peking Center for Life Sciences, Beijing, 100084, China.
  • 4 Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
  • 5 Tsinghua-Peking Center for Life Sciences, Beijing, 100084, China. hongwu@pku.edu.cn.
  • 6 School of Life Sciences, Peking University, Beijing, 100084, China. hongwu@pku.edu.cn.
  • 7 Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), South Medical University, Guangzhou, 510080, China. pengjiang@tsinghua.edu.cn.
  • 8 State Key Laboratory of Molecular Oncology, School of Life Sciences, Tsinghua University, Beijing, 100084, China. pengjiang@tsinghua.edu.cn.
  • 9 Tsinghua-Peking Center for Life Sciences, Beijing, 100084, China. pengjiang@tsinghua.edu.cn.
  • 10 State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Cell Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China. wenjingdu@ibms.pumc.edu.cn.
  • # Contributed equally.
PMID: 38263319 DOI: 10.1038/s41467-024-44772-8
Abstract

Many types of tumors feature aerobic glycolysis for meeting their increased energetic and biosynthetic demands. However, it remains still unclear how this glycolytic phenomenon is achieved and coordinated with other metabolic pathways in tumor cells in response to growth stimuli. Here we report that activation of Akt1 induces a metabolic switch to glycolysis from the Mitochondrial Metabolism via phosphorylation of cytoplasmic malic Enzyme 2 (ME2), named ME2fl (fl means full length), favoring an enhanced glycolytic phenotype. Mechanistically, in the cytoplasm, Akt1 phosphorylates ME2fl at serine 9 in the mitochondrial localization signal peptide at the N-terminus, preventing its mitochondrial translocation. Unlike mitochondrial ME2, which accounts for adjusting the tricarboxylic acid (TCA) cycle, ME2fl functions as a scaffold that brings together the key glycolytic Enzymes phosphofructokinase (PFKL), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Pyruvate Kinase M2 (PKM2), as well as Lactate Dehydrogenase A (LDHA), to promote glycolysis in the cytosol. Thus, through phosphorylation of ME2fl, Akt1 enhances the glycolytic capacity of tumor cells in vitro and in vivo, revealing an unexpected role for subcellular translocation switching of ME2 mediated by Akt1 in the metabolic adaptation of tumor cells to growth stimuli.

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