Identifying the target, mechanism, and agonist of α-ketoglutaric acid in delaying mesenchymal stem cell senescence.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-06-25 DOI:10.1016/j.celrep.2025.115917

Zhao Cui, Jiameng Li, Caifeng Li, Shiwen Deng, Wei Liu, Tong Lei, Junxian Cao, Ziyi Wang, Xiaoxu Wang, Shuhua Ma, Yinhua Zhu, Hongjun Yang, Peng Chen

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引用次数: 0

Abstract

α-ketoglutaric acid (AKG), a tricarboxylic acid cycle metabolite central to aerobic metabolism and longevity, retains unresolved anti-aging protein targets. Here, we demonstrate that reduced isocitrate dehydrogenase 1 (IDH1) expression during senescence lowers AKG production, accelerating the aging of mesenchymal stem cells (MSCs). Exogenous AKG or IDH1 overexpression restores AKG levels, enabling 2-oxoglutarate and Fe(II)-dependent oxygenase domain-containing protein 1 (OGFOD1)-catalyzed hydroxylation of ribosomal protein S23 (RPS23) at proline 62. Mechanistically, AKG stabilizes the OGFOD1-RPS23 complex, enhancing translation accuracy to limit misfolded protein accumulation while sustaining synthesis rates, thereby balancing proteostasis. The natural flavonoid scutellarin (Scu), identified as an IDH1 agonist, elevates AKG to delay MSC senescence. In aged mice, Scu improves cognitive function, reduces osteoporosis and skin aging, and suppresses senescence-associated secretory phenotype. Our findings identify the AKG-IDH1-RPS23 axis as a regulator of stem cell senescence and we propose metabolic reprogramming strategies for anti-aging therapies.

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α-酮戊二酸延缓间充质干细胞衰老的靶点、机制及激动剂的鉴定。

α-酮戊二酸（AKG）是一种三羧酸循环代谢物，对有氧代谢和长寿至关重要，它保留了尚未解决的抗衰老蛋白靶点。在这里，我们证明了衰老过程中异柠檬酸脱氢酶1 （IDH1）表达的减少会降低AKG的产生，加速间充质干细胞（MSCs）的衰老。外源性AKG或IDH1过表达恢复AKG水平，使2-氧葡萄糖酸盐和Fe（II）依赖的含氧酶结构域蛋白1 （OGFOD1）催化核糖体蛋白S23 （RPS23）在脯氨酸62位点的羟基化。从机制上讲，AKG稳定OGFOD1-RPS23复合物，提高翻译准确性，以限制错误折叠的蛋白质积累，同时维持合成速率，从而平衡蛋白质稳态。天然黄酮类黄芩素（Scu）被认为是一种IDH1激动剂，可提高AKG以延缓MSC衰老。在老年小鼠中，Scu可以改善认知功能，减少骨质疏松症和皮肤老化，并抑制衰老相关的分泌表型。我们的研究发现AKG-IDH1-RPS23轴是干细胞衰老的调节因子，我们提出了抗衰老治疗的代谢重编程策略。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.