马克斯·普朗克衰老生物学研究所Thomas Langer团队近日取得一项新成果。经过不懈努力，他们提出了核糖核酸与线粒体DNA的结合引起炎症。这一研究成果发表在2025年9月24日出版的国际学术期刊《自然》上。

在缺乏线粒体外切酶MGME14的motheme模型中，在老年小鼠的各种组织和缺乏线粒体i-AAA蛋白酶YME1L的细胞中，在年龄依赖性肾脏炎症期间，核苷酸失衡导致核糖核苷酸错误结合到mtDNA中增加。同样，在细胞周期阻滞的衰老细胞中，脱氧核糖核苷酸合成的减少增加了mtDNA的核糖核苷酸含量。这导致mtDNA释放到细胞质中，cGAS-STING激活和mtDNA依赖的衰老相关分泌表型（SASP），这可以被外源性添加的脱氧核糖核苷抑制。他们的结果强调了mtDNA对异常核糖核苷酸结合的敏感性，并表明不平衡的核苷酸代谢导致年龄和mtDNA依赖的炎症反应和衰老时的SASP。

研究人员表示，代谢失调可导致炎症反应。不平衡的核苷酸合成触发线粒体DNA （mtDNA）释放到细胞质中，并通过cGAS-STING信号传导引发先天免疫反应。然而，核苷酸缺乏如何驱动mtDNA依赖性炎症尚未阐明。

附：英文原文

Title: Ribonucleotide incorporation into mitochondrial DNA drives inflammation

Author: Bahat, Amir, Milenkovic, Dusanka, Cors, Eileen, Barnett, Mabel, Niftullayev, Sadig, Katsalifis, Athanasios, Schwill, Marc, Kirschner, Petra, MacVicar, Thomas, Giavalisco, Patrick, Jenninger, Louise, Clausen, Anders R., Paupe, Vincent, Prudent, Julien, Larsson, Nils-Gran, Rogg, Manuel, Schell, Christoph, Muylaert, Isabella, Lekholm, Erik, Nolte, Hendrik, Falkenberg, Maria, Langer, Thomas

Issue&Volume: 2025-09-24

Abstract: Metabolic dysregulation can lead to inflammatory responses1,2. Imbalanced nucleotide synthesis triggers the release of mitochondrial DNA (mtDNA) to the cytosol and an innate immune response through cGAS–STING signalling3. However, how nucleotide deficiency drives mtDNA-dependent inflammation has not been elucidated. Here we show that nucleotide imbalance leads to an increased misincorporation of ribonucleotides into mtDNA during age-dependent renal inflammation in a mouse model lacking the mitochondrial exonuclease MGME14, in various tissues of aged mice and in cells lacking the mitochondrial i-AAA protease YME1L. Similarly, reduced deoxyribonucleotide synthesis increases the ribonucleotide content of mtDNA in cell-cycle-arrested senescent cells. This leads to mtDNA release into the cytosol, cGAS–STING activation and the mtDNA-dependent senescence-associated secretory phenotype (SASP), which can be suppressed by exogenously added deoxyribonucleosides. Our results highlight the sensitivity of mtDNA to aberrant ribonucleotide incorporation and show that imbalanced nucleotide metabolism leads to age- and mtDNA-dependent inflammatory responses and SASP in senescence.

DOI: 10.1038/s41586-025-09541-7

Source: https://www.nature.com/articles/s41586-025-09541-7