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Nat Commun. 2016 Jun 6;7:11740. doi: 10.1038/ncomms11740.

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

Li X1,2,3, Cheng KKY1,2, Liu Z1,2, Yang JK4, Wang B1,2, Jiang X1,2, Zhou Y1,2, Hallenborg P5, Hoo RLC1,2, Lam KSL1,2, Ikeda Y6, Gao X3, Xu A1,2,7.

Author information

1
State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Pok Fu Lam, Hong Kong.
2
Department of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
3
Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 20032, China.
4
Beijing Key Laboratory of Diabetes Research and Care, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China.
5
Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense 5230, Denmark.
6
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
7
Department of Pharmacology &Pharmacy, The University of Hong Kong, Pok Fu Lam, 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.

PMID:
27265727
PMCID:
PMC4897763
DOI:
10.1038/ncomms11740
[Indexed for MEDLINE]
Free PMC Article

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