Division of Cancer Cell Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Department of Biological Sciences, School of Science, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
J Biochem. 2024 Jul 31;176(2):97-108. doi: 10.1093/jb/mvae032.
Senescent cells accumulate in various organs with ageing, and its accumulation induces chronic inflammation and age-related physiological dysfunctions. Several remodelling of intracellular environments have been identified in senescent cells, including enlargement of cell/nuclear size and intracellular acidification. Although these alterations of intracellular environments were reported to be involved in the unique characteristics of senescent cells, the contribution of intracellular acidification to senescence-associated cellular phenotypes is poorly understood. Here, we identified that the upregulation of TXNIP and its paralog ARRDC4 as a hallmark of intracellular acidification in addition to KGA-type GLS1. These genes were also upregulated in response to senescence-associated intracellular acidification. Neutralization of the intracellular acidic environment ameliorated not only senescence-related upregulation of TXNIP, ARRDC4 and KGA but also inflammation-related genes, possibly through suppression of PDK-dependent anaerobic glycolysis. Furthermore, we found that expression of the intracellular acidification-induced genes, TXNIP and ARRDC4, correlated with inflammatory gene expression in heterogeneous senescent cell population in vitro and even in vivo, implying that the contribution of intracellular pH to senescence-associated cellular features, such as SASP.
衰老过程中，衰老细胞会在各种器官中积累，其积累会引起慢性炎症和与年龄相关的生理功能障碍。已经鉴定出衰老细胞中存在几种细胞内环境的重塑，包括细胞/核大小的增大和细胞内酸化。尽管这些细胞内环境的改变被报道与衰老细胞的独特特征有关，但细胞内酸化对衰老相关细胞表型的贡献仍知之甚少。在这里，我们确定 TXNIP 和其同源物 ARRDC4 的上调以及 KGA 型 GLS1 的上调是细胞内酸化的标志之一。这些基因也会被衰老相关的细胞内酸化所上调。细胞内酸性环境的中和不仅改善了与衰老相关的 TXNIP、ARRDC4 和 KGA 的上调，还改善了与炎症相关的基因，这可能是通过抑制 PDK 依赖性无氧糖酵解来实现的。此外，我们发现细胞内酸化诱导基因 TXNIP 和 ARRDC4 的表达与体外甚至体内异质衰老细胞群体中炎症基因的表达相关，这表明细胞内 pH 值对衰老相关细胞特征（如 SASP）的贡献。
