Willemse Luciano, Terburgh Karin, Louw Roan
Mitochondria Research Group, Human Metabolomics, North-West University, Potchefstroom, South Africa.
Mitochondria Research Group, Human Metabolomics, North-West University, Potchefstroom, South Africa.
Biochim Biophys Acta Mol Basis Dis. 2025 Aug;1871(6):167873. doi: 10.1016/j.bbadis.2025.167873. Epub 2025 Apr 25.
Leigh syndrome is often caused by Ndufs4 mutations. The Ndufs4 knockout (KO) mouse model recapitulates key disease features, including systemic inflammation, neurodegeneration, and motor deficits. While dietary interventions such as the ketogenic diet show promise in mitigating mitochondrial dysfunction, conflicting results highlight uncertainties regarding its efficacy. Here, we evaluate the therapeutic potential of a polyunsaturated fatty acid (PUFA)-enriched high-fat diet (HFD) in Ndufs4 KO mice.
Dietary intervention began at postnatal day 23, with mice receiving either a normal diet (ND) or a HFD enriched with PUFAs. Phenotypic evaluation, including locomotor function, clasping behaviour, and survival, continued until natural death. In a second group of animals, biochemical analyses were conducted after three weeks on the diets, using Western blot to evaluate neurometabolic and inflammatory regulators, flow cytometry to quantify serum inflammation markers, and metabolic profiling to identify alterations in neurometabolism and the neurolipidome.
The HFD significantly extended lifespan and improved clasping behaviour in Ndufs4 KO mice but had no effect on locomotor activity or grip strength decline. While whole-brain mTOR (p70S6K1, 4E-BP1) and SIRT1 (PGC1-α, TNF-α) signalling pathways remained unaffected, the diet significantly reduced serum pro-inflammatory markers TNF and IL-6. Furthermore, the PUFA-enriched HFD partially restored disruptions in TCA cycle, ketone body, branched-chain amino acid, and lipid metabolism, indicating potential metabolic reprogramming.
Dietary interventions, such as a PUFA-enriched HFD, may alleviate systemic inflammation, partially correct metabolic imbalances, and mitigate specific disease phenotypes in Leigh syndrome, warranting further investigation into the underlying mechanisms and broader therapeutic applications.
Leigh综合征通常由Ndufs4突变引起。Ndufs4基因敲除（KO）小鼠模型重现了关键的疾病特征，包括全身炎症、神经退行性变和运动功能障碍。虽然生酮饮食等饮食干预措施在减轻线粒体功能障碍方面显示出前景，但相互矛盾的结果凸显了其疗效的不确定性。在此，我们评估富含多不饱和脂肪酸（PUFA）的高脂饮食（HFD）对Ndufs4基因敲除小鼠的治疗潜力。
饮食干预在出生后第23天开始，小鼠分别接受正常饮食（ND）或富含PUFA的HFD。表型评估，包括运动功能、紧握行为和生存率，持续至自然死亡。在第二组动物中，饮食三周后进行生化分析，使用蛋白质免疫印迹法评估神经代谢和炎症调节因子，流式细胞术量化血清炎症标志物，代谢谱分析确定神经代谢和神经脂质组的改变。
HFD显著延长了Ndufs4基因敲除小鼠的寿命并改善了紧握行为，但对运动活性或握力下降没有影响。虽然全脑mTOR（p70S6K1、4E-BP1）和SIRT1（PGC1-α、TNF-α）信号通路未受影响，但该饮食显著降低了血清促炎标志物TNF和IL-6。此外，富含PUFA的HFD部分恢复了三羧酸循环、酮体、支链氨基酸和脂质代谢的紊乱，表明可能存在代谢重编程。
饮食干预，如富含PUFA的HFD，可能减轻全身炎症，部分纠正代谢失衡，并减轻Leigh综合征的特定疾病表型，值得进一步研究其潜在机制和更广泛的治疗应用。
