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

TitleThe MDM2–p53–pyruvate carboxylase signalling axis couples mitochondrial metabolism to glucose-stimulated insulin secretion in pancreatic β-cells
Authors
Issue Date2016
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/ncomms/index.html
Citation
Nature Communications, 2016, v. 7, article no. 11740 How to Cite?
AbstractMitochondrial 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.
Persistent Identifierhttp://hdl.handle.net/10722/229307
ISSN
2023 Impact Factor: 14.7
2023 SCImago Journal Rankings: 4.887
PubMed Central ID
ISI Accession Number ID
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DC FieldValueLanguage
dc.contributor.authorLi, X-
dc.contributor.authorCheng, KY-
dc.contributor.authorLiu, Z-
dc.contributor.authorYang, J-
dc.contributor.authorWang, B-
dc.contributor.authorJiang, X-
dc.contributor.authorZhou, Y-
dc.contributor.authorHallenborg, P-
dc.contributor.authorHoo, RLC-
dc.contributor.authorLam, KSL-
dc.contributor.authorIkeda, Y-
dc.contributor.authorGao, X-
dc.contributor.authorXu, A-
dc.date.accessioned2016-08-23T14:10:18Z-
dc.date.available2016-08-23T14:10:18Z-
dc.date.issued2016-
dc.identifier.citationNature Communications, 2016, v. 7, article no. 11740-
dc.identifier.issn2041-1723-
dc.identifier.urihttp://hdl.handle.net/10722/229307-
dc.description.abstractMitochondrial 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.-
dc.languageeng-
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/ncomms/index.html-
dc.relation.ispartofNature Communications-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleThe MDM2–p53–pyruvate carboxylase signalling axis couples mitochondrial metabolism to glucose-stimulated insulin secretion in pancreatic β-cells-
dc.typeArticle-
dc.identifier.emailCheng, KY: dorncky@hkucc.hku.hk-
dc.identifier.emailJiang, X: xue0129@hku.hk-
dc.identifier.emailZhou, Y: zhouyaw@hku.hk-
dc.identifier.emailHoo, RLC: rubyhoo@hkucc.hku.hk-
dc.identifier.emailLam, KSL: ksllam@hku.hk-
dc.identifier.emailXu, A: amxu@hkucc.hku.hk-
dc.identifier.authorityCheng, KY=rp01672-
dc.identifier.authorityHoo, RLC=rp01334-
dc.identifier.authorityLam, KSL=rp00343-
dc.identifier.authorityXu, A=rp00485-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1038/ncomms11740-
dc.identifier.pmid27265727-
dc.identifier.pmcidPMC4897763-
dc.identifier.scopuseid_2-s2.0-84973370407-
dc.identifier.hkuros261662-
dc.identifier.volume7-
dc.identifier.spagearticle no. 11740-
dc.identifier.epagearticle no. 11740-
dc.identifier.isiWOS:000377384100001-
dc.publisher.placeUnited Kingdom-
dc.relation.projectA Multi-disciplinary Approach to Investigate Vascular Dysfunction in Obesity and Diabetes: From Molecular Mechanism to Therapeutic Intervention-
dc.identifier.issnl2041-1723-

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