磷酸化
磷酸蛋白质组学
细胞生物学
PI3K/AKT/mTOR通路
下调和上调
生物
细胞凋亡
福克斯O1
信号转导
基因敲除
蛋白质磷酸化
癌症研究
蛋白激酶B
蛋白激酶A
生物化学
基因
作者
Qiuyu Li,Xiaolan Lin,Xiaowen Bo,Siyuan Chen,Dongzhi Zhao,Qian Ma,Yanping Zhao,Ying Hong,Jinghua Liu,Qingyu Fan
出处
期刊:The Journals of Gerontology
[Oxford University Press]
日期:2024-01-08
卷期号:79 (3)
标识
DOI:10.1093/gerona/glae003
摘要
Abstract The mechanisms through which aging increases heart injury remain partially understood. Protein phosphorylation plays a critical regulatory role in cell survival and death. Using an unbiased phosphoproteomics approach, we aimed to identify the proteins whose phosphorylation could be causatively related to aging-related cardiomyocyte apoptosis and elucidate the underlying mechanisms. Comparative phosphoproteomics was conducted on cardiac tissues obtained from young (8 weeks) and aged (24 months) mice. Our findings revealed that the Mammalian Target of Rapamycin phosphorylation at T1262 (mTORT1262) was reduced in the aging heart. Immunohistochemical and Western blot analyses confirmed these findings in aging myocardia and D-galactose-induced senescent AC16 cardiomyocytes. In hypoxia/reoxygenation cardiomyocytes, mTORT1262 phosphorylation deficiency (mTORT1262A, lentivirus-mediated transfection) inhibited AKT1, suppressed NF-κB, activated FOXO1/3a signaling, and ultimately exacerbated apoptosis. Conversely, mTORT1262 pseudophosphorylation (mTORT1262E) exhibited opposite effects. Through bioinformatics and CO-IP, purinergic receptor P2X4 (P2X4R) was found to be the possible receptor responsible for mTORT1262 phosphorylation. Knockdown of P2X4R increased apoptosis, whereas its overexpression decreased it. In senescent cardiomyocytes, P2X4R expression and mTORT1262 and AKT1S473 phosphorylation were reduced, NF-κB signaling was suppressed, and FOXO1/3a signaling was activated. We demonstrated that P2X4R downregulation and the subsequent reduction of mTORT1262 phosphorylation is a novel mechanism contributing to cardiomyocyte apoptosis in aging hearts. The P2X4R-mTOR-AKT1 signaling pathway represents a potential therapeutic target against accelerated cardiac injury in aging.
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