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

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 H Ikeda, Xin Gao, Aimin Xu

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish (US)
Article number11740
JournalNature Communications
Volume7
DOIs
StatePublished - Jun 6 2016

Fingerprint

Pyruvate Carboxylase
pyruvates
insulin
secretions
metabolism
Metabolism
glucose
Insulin
Glucose
cells
homeostasis
Homeostasis
mice
Pharmacology
Oxaloacetic Acid
Chemical activation
activation
Glucose Intolerance
oxygen consumption
deletion

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

The MDM2-p53-pyruvate carboxylase signalling axis couples mitochondrial metabolism to glucose-stimulated insulin secretion in pancreatic β-cells. / Li, Xiaomu; Cheng, Kenneth K Y; Liu, Zhuohao; Yang, Jin Kui; Wang, Baile; Jiang, Xue; Zhou, Yawen; Hallenborg, Philip; Hoo, Ruby L C; Lam, Karen S L; Ikeda, Yasuhiro H; Gao, Xin; Xu, Aimin.

In: Nature Communications, Vol. 7, 11740, 06.06.2016.

Research output: Contribution to journalArticle

Li, X, Cheng, KKY, Liu, Z, Yang, JK, Wang, B, Jiang, X, Zhou, Y, Hallenborg, P, Hoo, RLC, Lam, KSL, Ikeda, YH, Gao, X & Xu, A 2016, 'The MDM2-p53-pyruvate carboxylase signalling axis couples mitochondrial metabolism to glucose-stimulated insulin secretion in pancreatic β-cells', Nature Communications, vol. 7, 11740. https://doi.org/10.1038/ncomms11740
Li, Xiaomu ; Cheng, Kenneth K Y ; Liu, Zhuohao ; Yang, Jin Kui ; Wang, Baile ; Jiang, Xue ; Zhou, Yawen ; Hallenborg, Philip ; Hoo, Ruby L C ; Lam, Karen S L ; Ikeda, Yasuhiro H ; Gao, Xin ; Xu, Aimin. / The MDM2-p53-pyruvate carboxylase signalling axis couples mitochondrial metabolism to glucose-stimulated insulin secretion in pancreatic β-cells. In: Nature Communications. 2016 ; Vol. 7.
@article{78e1e925d1254461bf72e226b3f188da,
title = "The MDM2-p53-pyruvate carboxylase signalling axis couples mitochondrial metabolism to glucose-stimulated insulin secretion in pancreatic β-cells",
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.",
author = "Xiaomu Li and Cheng, {Kenneth K Y} and Zhuohao Liu and Yang, {Jin Kui} and Baile Wang and Xue Jiang and Yawen Zhou and Philip Hallenborg and Hoo, {Ruby L C} and Lam, {Karen S L} and Ikeda, {Yasuhiro H} and Xin Gao and Aimin Xu",
year = "2016",
month = "6",
day = "6",
doi = "10.1038/ncomms11740",
language = "English (US)",
volume = "7",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - The MDM2-p53-pyruvate carboxylase signalling axis couples mitochondrial metabolism to glucose-stimulated insulin secretion in pancreatic β-cells

AU - Li, Xiaomu

AU - Cheng, Kenneth K Y

AU - Liu, Zhuohao

AU - Yang, Jin Kui

AU - Wang, Baile

AU - Jiang, Xue

AU - Zhou, Yawen

AU - Hallenborg, Philip

AU - Hoo, Ruby L C

AU - Lam, Karen S L

AU - Ikeda, Yasuhiro H

AU - Gao, Xin

AU - Xu, Aimin

PY - 2016/6/6

Y1 - 2016/6/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84973370407&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84973370407&partnerID=8YFLogxK

U2 - 10.1038/ncomms11740

DO - 10.1038/ncomms11740

M3 - Article

C2 - 27265727

AN - SCOPUS:84973370407

VL - 7

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 11740

ER -