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

• 成果类型: Article
• 署名作者: Yang, Yumei; Wang, Baomin; Dong, Haoru; Lin, Huige; Ho, Melody Yuen-man; Hu, Ke; Zhang, Na; Ma, Jing; Xie, Rong; Cheng, Kenneth King-yip; Li, Xiaomu
• 署名单位: Fudan University; Fudan University; Hong Kong Polytechnic University; Hong Kong Polytechnic University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11327
• DOI: 10.1073/pnas.2401218121
• 发表日期: 2024-10-29
• 关键词: insulin-secretion; glucose; islets; proliferation; metabolism; promotes; dehydrogenase; anaplerosis; deficiency; DYNAMICS

摘要

Defective glucose- stimulated insulin secretion (GSIS) and (3- cell senescence are hallmarks in diabetes. The mitochondrial enzyme pyruvate carboxylase (PC) has been shown to promote GSIS and (3- cell proliferation in the clonal (3- cell lines, yet its physiological relevance remains unknown. Here, we provide animal and human data showing a role of PC in protecting (3- cells against senescence and maintaining GSIS under different physiological and pathological conditions. (3- cell- specific deletion of PC impaired GSIS and induced (3- 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 hyperglycemiaand aging- induced p53- related senescence in human and mouse islets as well as INS- 1E (3- 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 (3- 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 (3- cell senescence through the MDM2-p53 axis.