线粒体代谢和表观遗传串扰驱动SASP
Mitochondrial metabolism and epigenetic crosstalk drive SASP.
摘要(中文译文)
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。胞质线粒体核酸激活先天免疫信号，从而启动这一炎症程序。在此，我们发现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的可利用性，以支持SASP基因上的组蛋白乙酰化。线粒体DNA驱动的信号激活炎症转录因子，而乙酰辅酶A的可利用性则是SASP基因强劲转录所必需的。因此，提高乙酰辅酶A水平可促进SASP基因表达，而抑制SLC25A1（线粒体柠檬酸外排体）则会降低SASP位点的组蛋白乙酰化，限制该程序的活性。在体内，抑制SLC25A1可降低SASP位点的染色质可及性，减轻炎症并改善老年小鼠的健康寿命。总之，这些发现揭示了一个线粒体代谢检查点，使先天免疫信号得以通过表观遗传方式执行，阐明了一种选择性调控衰老细胞炎症输出的机制。
Abstract
Senescent cells promote tissue dysfunction in part through the senescence-associated secretory phenotype (SASP). Cytosolic mitochondrial nucleic acids activate innate immune signalling to initiate this inflammatory programme. 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.
如何引用
AMA
Hélène Martini, Jodie Birch, Francisco D M Marques, Stella Victorelli, Anthony B Lagnado, Nicholas Pirius, et al. Mitochondrial metabolism and epigenetic crosstalk drive SASP.. Nature. 2026; doi:10.1038/s41586-026-10791-2.
APA
Hélène Martini, Jodie Birch, Francisco D M Marques, Stella Victorelli, Anthony B Lagnado, Nicholas Pirius, et al (2026). Mitochondrial metabolism and epigenetic crosstalk drive SASP.. Nature. https://doi.org/10.1038/s41586-026-10791-2
GB/T 7714
Hélène Martini, Jodie Birch, Francisco D M Marques, Stella Victorelli, Anthony B Lagnado, Nicholas Pirius, et al. Mitochondrial metabolism and epigenetic crosstalk drive SASP.[J]. Nature, 2026 doi:10.1038/s41586-026-10791-2.
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