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The MDM2–p53–pyruvate carboxylase signalling axis couples mitochondrial metabolism to glucose-stimulated insulin secretion in pancreatic β-cells

Author

Listed:
  • Xiaomu Li

    (State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong
    The University of Hong Kong
    Zhongshan Hospital, Fudan University)

  • Kenneth K. Y. Cheng

    (State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong
    The University of Hong Kong)

  • Zhuohao Liu

    (State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong
    The University of Hong Kong)

  • Jin-Kui Yang

    (Beijing Key Laboratory of Diabetes Research and Care, Beijing Tongren Hospital, Capital Medical University)

  • Baile Wang

    (State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong
    The University of Hong Kong)

  • Xue Jiang

    (State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong
    The University of Hong Kong)

  • Yawen Zhou

    (State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong
    The University of Hong Kong)

  • Philip Hallenborg

    (University of Southern Denmark)

  • Ruby L. C. Hoo

    (State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong
    The University of Hong Kong)

  • Karen S. L. Lam

    (State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong
    The University of Hong Kong)

  • Yasuhiro Ikeda

    (Mayo Clinic)

  • Xin Gao

    (Zhongshan Hospital, Fudan University)

  • Aimin Xu

    (State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong
    The University of Hong Kong
    The University of Hong Kong)

Abstract

Mitochondrial metabolism is pivotal for glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells. However, little is known about the molecular machinery that controls the homeostasis of intermediary metabolites in mitochondria. Here we show that the activation of p53 in β-cells, by genetic deletion or pharmacological inhibition of its negative regulator MDM2, impairs GSIS, leading to glucose intolerance in mice. Mechanistically, p53 activation represses the expression of the mitochondrial enzyme pyruvate carboxylase (PC), resulting in diminished production of the TCA cycle intermediates oxaloacetate and NADPH, and impaired oxygen consumption. The defective GSIS and mitochondrial metabolism in MDM2-null islets can be rescued by restoring PC expression. Under diabetogenic conditions, MDM2 and p53 are upregulated, whereas PC is reduced in mouse β-cells. Pharmacological inhibition of p53 alleviates defective GSIS in diabetic islets by restoring PC expression. Thus, the MDM2–p53–PC signalling axis links mitochondrial metabolism to insulin secretion and glucose homeostasis, and could represent a therapeutic target in diabetes.

Suggested Citation

  • Xiaomu Li & Kenneth K. Y. Cheng & Zhuohao Liu & Jin-Kui Yang & Baile Wang & Xue Jiang & Yawen Zhou & Philip Hallenborg & Ruby L. C. Hoo & Karen S. L. Lam & Yasuhiro Ikeda & Xin Gao & Aimin Xu, 2016. "The MDM2–p53–pyruvate carboxylase signalling axis couples mitochondrial metabolism to glucose-stimulated insulin secretion in pancreatic β-cells," Nature Communications, Nature, vol. 7(1), pages 1-14, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11740
    DOI: 10.1038/ncomms11740
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    Cited by:

    1. Kelvin Ka-lok Wu & Xiaofan Xu & Manyin Wu & Xiaomu Li & Moinul Hoque & Gloria Hoi Yee Li & Qizhou Lian & Kekao Long & Tongxi Zhou & Hailong Piao & Aimin Xu & Hannah Xiaoyan Hui & Kenneth King-yip Chen, 2024. "MDM2 induces pro-inflammatory and glycolytic responses in M1 macrophages by integrating iNOS-nitric oxide and HIF-1α pathways in mice," Nature Communications, Nature, vol. 15(1), pages 1-21, December.

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