ArticleProceedings of the National Academy of Sciences of the United States of America2024
The mitochondrial enzyme pyruvate carboxylase restricts pancreatic β-cell senescence by blocking p53 activation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers, 1 of them a synthesis that pooled it.
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Who cites it
11 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Cross-Study Meta-Analysis of Blood Transcriptomes in Type 2 Diabetes.International journal of molecular sciences · 2025Pooled it
- CBX4 stabilizes NEUROD1 through SUMO-ubiquitin crosstalk to delay β-cell senescence.Nature communications · 2026Article
- Liver-specific delivery of MDM2 antisense oligonucleotides counteracts diet-induced metabolic-dysfunction-associated steatotic liver diseases.Molecular therapy. Nucleic acids · 2026Article
- Branched-chain α-keto acids impair glucose-stimulated insulin secretion in pancreatic β-cells under diabetes by reactivating the LDHA-lactate axis.Nature communications · 2026Article
- Formononetin inhibits p53 signaling pathway activation to delay cellular senescence and ameliorates diabetic kidney disease.World journal of diabetes · 2026Article
- Nucleolar stress facilitates islet β cell senescence via hijacking the DNA damage response pathways.iScience · 2025Article
- Article
- Taurine Alleviates Pancreatic β-Cell Senescence by Inhibition of p53 Pathway.Journal of diabetes · 2025Article
- Pyruvate Carboxylase as a Moonlighting Metabolic Enzyme Protects β-Cell From Senescence.Journal of diabetes · 2025Article
- Article
- The mitochondrial enzyme pyruvate carboxylase restricts pancreatic β-cell senescence by blocking p53 activation.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
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11 authors.
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Abstract
Defective glucose-stimulated insulin secretion (GSIS) and β-cell senescence are hallmarks in diabetes. The mitochondrial enzyme pyruvate carboxylase (PC) has been shown to promote GSIS and β-cell proliferation in the clonal β-cell lines, yet its physiological relevance remains unknown. Here, we provide animal and human data showing a role of PC in protecting β-cells against senescence and maintaining GSIS under different physiological and pathological conditions. β-cell-specific deletion of PC impaired GSIS and induced β-cell senescence in the mouse models under either a standard chow diet or prolonged high-fat diet feeding. Transcriptomic analysis indicated that p53-related senescence and cell cycle arrest are activated in PC-deficient islets. Overexpression of PC inhibited hyperglycemia- and aging-induced p53-related senescence in human and mouse islets as well as INS-1E β-cells, whereas knockdown of PC provoked senescence. Mechanistically, PC interacted with MDM2 to prevent its degradation via the MDM2 binding motif, which in turn restricts the p53-dependent senescent program in β-cells. On the contrary, the regulatory effects of PC on GSIS and the tricarboxylic acid (TCA) anaplerotic flux are p53-independent. We illuminate a function of PC in controlling β-cell senescence through the MDM2-p53 axis.
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