The MDM2-p53-pyruvate carboxylase signalling axis couples mitochondrial metabolism to glucose-stimulated insulin secretion in pancreatic β-cells.
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.
State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Pok Fu Lam, Hong Kong.|Department of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.|Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 20032, China.
Xiaomu
X
Li
State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Pok Fu Lam, Hong Kong.|Department of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
Kenneth K Y
KKY
Cheng
State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Pok Fu Lam, Hong Kong.|Department of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
Zhuohao
Z
Liu
Beijing Key Laboratory of Diabetes Research and Care, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China.
Jin-Kui
JK
Yang
State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Pok Fu Lam, Hong Kong.|Department of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
Baile
B
Wang
State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Pok Fu Lam, Hong Kong.|Department of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
Xue
X
Jiang
State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Pok Fu Lam, Hong Kong.|Department of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
Yawen
Y
Zhou
Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense 5230, Denmark.
Philip
P
Hallenborg
State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Pok Fu Lam, Hong Kong.|Department of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
Ruby L C
RLC
Hoo
State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Pok Fu Lam, Hong Kong.|Department of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
Karen S L
KSL
Lam
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
Yasuhiro
http://orcid.org/0000-0002-9874-7537
Y
Ikeda
Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 20032, China.
Xin
X
Gao
State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Pok Fu Lam, Hong Kong.|Department of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.|Department of Pharmacology &Pharmacy, The University of Hong Kong, Pok Fu Lam, Hong Kong.
Aimin
A
Xu
D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D009928:Organ Specificity; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D011766:Pyruvate Carboxylase / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D007093:Imidazoles; D007328:Insulin; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D051736:Proto-Oncogene Proteins c-mdm2; D011766:Pyruvate Carboxylase; D005947:Glucose