线粒体代谢和表观遗传串扰驱动SASP
线粒体代谢和表观遗传串扰驱动SASP
作者： 小柯机器人 发布时间：2026/7/30 17:27:37
本期文章：《自然》：Online/在线发表
美国梅奥诊所João F. Passos小组取得一项新突破。他们研究出线粒体代谢和表观遗传串扰驱动SASP。2026年7月29日出版的《自然》发表了这项成果。
在这里，该研究组表明线粒体代谢提供了第二层控制，使炎症程序得以执行。在衰老细胞中，线粒体丙酮酸-柠檬酸-乙酰辅酶A轴上调，增加了乙酰辅酶A的可用性，以支持SASP基因上的组蛋白乙酰化。线粒体DNA驱动的信号可以激活炎症转录因子，而SASP基因的自动转录需要乙酰辅酶a的可用性。因此，乙酰辅酶A水平的提高促进了SASP基因的表达，而抑制SLC25A1（线粒体柠檬酸出口者）会降低SASP位点的组蛋白乙酰化，从而限制了该程序的活性。在体内，抑制SLC25A1降低了SASP位点的染色质可及性，抑制炎症并改善老年小鼠的健康寿命。总之，这些发现确定了一个线粒体代谢检查点，它使先天免疫信号的表观遗传执行成为可能，揭示了一种选择性控制衰老细胞炎症输出的机制。
研究人员表示，衰老细胞部分通过衰老相关分泌表型（SASP）促进组织功能障碍。细胞质线粒体核酸激活先天免疫信号，启动这种炎症程序。
附：英文原文
Title: Mitochondrial metabolism and epigenetic crosstalk drive SASP
Author: Martini, Hlne, Birch, Jodie, Marques, Francisco D. M., Victorelli, Stella, Lagnado, Anthony B., Pirius, Nicholas, Franco, Ana Catarina, Lee, Gung, Han, Yeaeun, Rowsey, Jennifer L., Ismail, Wazim Mohammed, Mazzone, Amelia, Espe, Tianna M., Hitosugi, Taro, Li, Ya, Washington, Alexander M., Havas, Aaron, Murad, Rabi, Lei, Xue, Porritt, Rebecca A., Maddocks, Oliver D. K., Machado Espindola-Netto, Jair, Saul, Dominik, Khosla, Sundeep, Jurk, Diana, Kostallari, Enis, Gaspar-Maia, Alexandre, Adams, Peter D., Passos, Joo F.
Issue&Volume: 2026-07-29
Abstract: Senescent cells promote tissue dysfunction in part through the senescence-associated secretory phenotype (SASP)1. Cytosolic mitochondrial nucleic acids activate innate immune signalling to initiate this inflammatory programme2,3. Here we show that mitochondrial metabolism provides a second layer of control that enables execution of the inflammatory programme. In senescent cells, the mitochondrial pyruvate–citrate–acetyl-CoA axis is upregulated, increasing the availability of acetyl-CoA to support histone acetylation at SASP genes. Whereas mitochondrial DNA-driven signalling activates inflammatory transcription factors, acetyl-CoA availability is required for robust transcription of SASP genes. Accordingly, enhancing acetyl-CoA levels promotes SASP gene expression, whereas inhibition of SLC25A1, the mitochondrial citrate exporter, reduces histone acetylation at SASP loci, limiting activity of this programme. In vivo, inhibition of SLC25A1 reduces chromatin accessibility at SASP loci, dampens inflammation and improves healthspan in aged mice. Together, these findings identify a mitochondrial metabolic checkpoint that enables the epigenetic execution of innate immune signalling, revealing a mechanism that selectively controls the inflammatory output of senescent cells.
DOI: 10.1038/s41586-026-10791-2
Source: https://www.nature.com/articles/s41586-026-10791-2