Terburgh Karin, Sweeney Nastassja, Louw Roan
Human Metabolomics, Faculty of Natural and Agricultural Sciences, North-West University, (Potchefstroom Campus), Private Bag, Potchefstroom, X6001, South Africa.
Metabolomics. 2025 Jun 11;21(4):76. doi: 10.1007/s11306-025-02275-7.
Mitochondrial complex (CI) deficiency frequently manifests as a severe neurometabolic disorder called Leigh syndrome (LS). Research on the Ndufs4 knockout (KO) mouse model has identified neuronal vulnerability to CI deficiency as a major driver of the disease, yet its effects on hepatic function remain unclear. Considering the importance of the liver, and its interconnection with the brain, in regulating whole-body metabolic balance, further investigation into the effects of whole-body Ndufs4 KO on the liver is warranted.
This study investigated liver bioenergetics and metabolism in Ndufs4 KO and WT mice at the late stage of LS.
Bioenergetic investigations of liver mitochondria (n ≥ 3) included spectrophotometric respiratory chain enzyme (CI-IV) activity assays and high-resolution respirometry. Hypothesis-generating metabolomics of whole-liver extracts (n ≥ 19) utilised H-NMR, GC-TOFMS, and LC-MS/MS. Significant alterations were identified via t-tests and effect size calculations.
Ndufs4 KO livers displayed a significant ~ 86% reduction in CI activity and a ~ 43% decrease in CI contribution to CI + II-driven respiration. CII-driven respiration remained unaffected, providing the predominant electron flux in both genotypes. Metabolic profiling revealed widespread perturbations in Ndufs4 KO hepatic metabolism including glucose-, amino acid-, purine/pyrimidine metabolism and the TCA-cycle.
Despite severe CI deficiency, respiration in the Ndufs4 KO liver remains largely unaffected due to reliance on CII. Nonetheless, advanced LS significantly disrupts liver metabolism, with O-GlcNAcylation and mTOR signalling suggestsed as key areas for future investigation. Altogether, our findings underscore the importance of interorgan metabolic dynamics and the liver-brain axis in neurometabolic disorders like LS.
线粒体复合物I（CI）缺乏症常表现为一种严重的神经代谢紊乱疾病，称为 Leigh 综合征（LS）。对 Ndufs4 基因敲除（KO）小鼠模型的研究已确定神经元对 CI 缺乏的易感性是该疾病的主要驱动因素，但其对肝功能的影响仍不清楚。鉴于肝脏在调节全身代谢平衡中的重要性及其与大脑的相互联系，有必要进一步研究全身 Ndufs4 基因敲除对肝脏的影响。
本研究调查了 LS 晚期 Ndufs4 基因敲除小鼠和野生型（WT）小鼠的肝脏生物能量学和代谢情况。
对肝脏线粒体（n≥3）进行生物能量学研究，包括分光光度法呼吸链酶（CI-IV）活性测定和高分辨率呼吸测定法。利用氢核磁共振（H-NMR）、气相色谱-飞行时间质谱（GC-TOFMS）和液相色谱-串联质谱（LC-MS/MS）对全肝提取物（n≥19）进行假设生成代谢组学分析。通过 t 检验和效应量计算确定显著变化。
Ndufs4 基因敲除小鼠的肝脏 CI 活性显著降低约 86%，CI 对 CI+II 驱动呼吸的贡献降低约 43%。CII 驱动的呼吸不受影响，是两种基因型中主要的电子通量。代谢谱分析显示，Ndufs4 基因敲除小鼠的肝脏代谢存在广泛紊乱，包括葡萄糖、氨基酸、嘌呤/嘧啶代谢和三羧酸循环。
尽管存在严重的 CI 缺乏，但由于对 CII 的依赖，Ndufs4 基因敲除小鼠肝脏的呼吸在很大程度上仍未受影响。然而，晚期 LS 显著扰乱肝脏代谢，O-连接的 N-乙酰葡糖胺糖基化（O-GlcNAcylation）和雷帕霉素靶蛋白（mTOR）信号通路被认为是未来研究的关键领域。总之，我们的研究结果强调了器官间代谢动态以及肝脏-大脑轴在 LS 等神经代谢疾病中的重要性。
