Zhang Mengmeng, Lv Hong, Bai Xiaoyin, Ruan Gechong, Li Qing, Lin Kai, Yang Hong, Qian Jiaming
Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Pathology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Beijing, China.
Immun Ageing. 2025 Jan 10;22(1):4. doi: 10.1186/s12979-024-00494-5.
The characteristics of ulcerative colitis (UC) in the elderly are quite different from the young population. Mitochondrial injury is a key mechanism regulating both aging and inflammation. This study aims to reveal the role of mitochondrial damage in the pathogenesis of adult- and elderly-onset UC.
RNA-sequencing of colonic mucosa from adult- and elderly-onset UC patients was performed. Mitochondria-related differentially expressive genes (mDEGs) and immune cell infiltration analysis were identified and performed in colonic tissues from UC patients. Mice aged 6-8 weeks and 20-24 months were administered 2% dextran sodium sulphate (DSS) for 7 days to induce colitis. Mitochondrial morphological changes and ATP levels were evaluated in the colons of mice. Mechanistically, we explored the association of key mDEG with reactive oxygen species (ROS), oxygen consumption rates, NLRP3/IL-1β pathway in HCT116 cell line.
Thirty mDEGs were identified between adult- and elderly-onset UC, which were related primarily to mitochondrial respiratory function and also had significant correlation with different infiltrates of immune cells. Compared with young colitis mice, DSS-induced colitis in the aged mice exhibited more severe inflammation, damaged mitochondrial structure and lower ATP levels in colonic tissues. ALDH1L1 was identified as a hub DEG through protein-protein interaction networks of RNA-seq, which was downregulated in UC patients or colitis mice versus healthy controls. In tumor necrosis factor-alpha-stimulated HCT116 cells, mitochondrial ROS, NLRP3 and IL-1β expression increased less and mitochondrial respiration had an upregulated trend after knocking down ALDH1L1.
There are significant differences in mitochondrial structure, ATP production and mitochondria-related gene expression between adult- and elderly-onset UC, which have a potential link with cytokine pathways and immune microenvironment. The more prominent mitochondrial injury may be a key factor for more severe inflammatory response and poorer outcome in elderly-onset UC.
老年溃疡性结肠炎（UC）的特征与年轻人群有很大不同。线粒体损伤是调节衰老和炎症的关键机制。本研究旨在揭示线粒体损伤在成人及老年起病的UC发病机制中的作用。
对成人及老年起病的UC患者的结肠黏膜进行RNA测序。在UC患者的结肠组织中鉴定并进行线粒体相关差异表达基因（mDEG）和免疫细胞浸润分析。给6 - 8周龄和20 - 24月龄的小鼠给予2%葡聚糖硫酸钠（DSS）7天以诱导结肠炎。评估小鼠结肠中的线粒体形态变化和ATP水平。从机制上，我们在HCT116细胞系中探索了关键mDEG与活性氧（ROS）、氧消耗率、NLRP3/IL - 1β途径的关联。
在成人及老年起病的UC之间鉴定出30个mDEG，它们主要与线粒体呼吸功能相关，并且与免疫细胞的不同浸润也有显著相关性。与年轻的结肠炎小鼠相比，DSS诱导的老年小鼠结肠炎表现出更严重的炎症、受损的线粒体结构以及结肠组织中更低的ATP水平。通过RNA测序的蛋白质 - 蛋白质相互作用网络鉴定出ALDH1L1为核心DEG，在UC患者或结肠炎小鼠中与健康对照相比其表达下调。在肿瘤坏死因子 - α刺激的HCT116细胞中，敲低ALDH1L1后线粒体ROS、NLRP3和IL - 1β表达增加较少，线粒体呼吸有上调趋势。
成人及老年起病的UC在线粒体结构、ATP产生和线粒体相关基因表达方面存在显著差异，这与细胞因子途径和免疫微环境有潜在联系。更突出的线粒体损伤可能是老年起病的UC中更严重炎症反应和更差预后的关键因素。
