The mitochondrial enzyme pyruvate carboxylase restricts pancreatic β-cell senescence by blocking p53 activation.

Autor:	Yang Y; Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200030, China., Wang B; Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200030, China., Dong H; Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200030, China., Lin H; Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong 999077, China.; The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518000, China., Yuen-Man Ho M; Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong 999077, China., Hu K; Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200030, China., Zhang N; Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200030, China., Ma J; Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200030, China., Xie R; Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200030, China., Cheng KK; Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong 999077, China.; The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518000, China., Li X; Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200030, China.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Oct 29; Vol. 121 (44), pp. e2401218121. Date of Electronic Publication: 2024 Oct 22.
DOI:	10.1073/pnas.2401218121
Abstrakt:	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. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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