Suzuki Naoki, Shibata Shoichiro, Sugimoto Masahiro, Elmer Eskil, Uchino Hiroyuki
Department of Anesthesiology, Tokyo Medical University, Tokyo 1600023, Japan.
Institute for Advanced Biosciences, Keio University, Tsuruoka 9970052, Japan.
Metabolites. 2025 Sep 9;15(9):600. doi: 10.3390/metabo15090600.
: Sepsis is a life-threatening condition characterized by organ dysfunction due to a dysregulated host response to infection. Mitochondrial dysfunction is considered a key contributor to the pathogenesis of sepsis, but its molecular mechanisms remain unclear. : In this study, we used a cecal ligation and puncture (CLP) model to induce sepsis in wild-type (WT) and cyclophilin D knockout (CypD KO) mice. Liver tissues were collected at 0, 6, and 18 h post-CLP and analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). : Metabolomic profiling revealed that lactate levels significantly increased in the WT mice but remained stable in the KO mice. While AMP levels were preserved in the KO mice, these mice had significantly higher glutathione disulfide (GSSG) and spermidine concentrations than the WT mice at 18 h ( < 0.05). The levels of malondialdehyde (MDA), a marker of oxidative stress, were also significantly lower in the KO mice at 18 h ( < 0.05). These findings suggest that CypD deficiency preserves mitochondrial function, enhances resistance to oxidative stress, and mitigates septic liver injury. Our results highlight the potential of targeting mitochondrial permeability transition as a therapeutic strategy for sepsis.
脓毒症是一种危及生命的病症，其特征为宿主对感染的反应失调导致器官功能障碍。线粒体功能障碍被认为是脓毒症发病机制的关键因素，但其分子机制仍不清楚。在本研究中，我们使用盲肠结扎穿刺（CLP）模型在野生型（WT）和亲环素D基因敲除（CypD KO）小鼠中诱导脓毒症。在CLP后0、6和18小时收集肝脏组织，并使用液相色谱-串联质谱（LC-MS/MS）进行分析。代谢组学分析显示，WT小鼠中的乳酸水平显著升高，而KO小鼠中的乳酸水平保持稳定。虽然KO小鼠中的AMP水平得以维持，但在18小时时，这些小鼠的谷胱甘肽二硫化物（GSSG）和亚精胺浓度显著高于WT小鼠（<0.05）。氧化应激标志物丙二醛（MDA）的水平在18小时时在KO小鼠中也显著较低（<0.05）。这些发现表明，CypD缺乏可保留线粒体功能、增强对氧化应激的抵抗力并减轻脓毒症性肝损伤。我们的结果突出了将线粒体通透性转换作为脓毒症治疗策略的潜力。
