Perna Laura, Salsbury Grace, Dushti Mohammed, Smith Christopher J, Morales Valle, Bianchi Katiuscia, Czibik Gabor, Chapple J Paul
William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
Pharmacology & Toxicology Department, Faculty of Medicine, Kuwait University, Kuwait City P.O. Box 24923, Kuwait.
Int J Mol Sci. 2024 Dec 10;25(24):13242. doi: 10.3390/ijms252413242.
Mitochondrial dysfunction is implicated in the pathogenesis of the neurological condition autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), yet precisely how the mitochondrial metabolism is affected is unknown. Thus, to better understand changes in the mitochondrial metabolism caused by loss of the sacsin protein (encoded by the SACS gene, which is mutated in ARSACS), we performed mass spectrometry-based tracer analysis, with both glucose- and glutamine-traced carbon. Comparing the metabolite profiles between wild-type and sacsin-knockout cell lines revealed increased reliance on aerobic glycolysis in sacsin-deficient cells, as evidenced by the increase in lactate and reduction of glucose. Moreover, sacsin knockout cells differentiated towards a neuronal phenotype had increased levels of tricarboxylic acid cycle metabolites relative to the controls. We also observed disruption in the glutaminolysis pathway in differentiated and undifferentiated cells in the absence of sacsin. In conclusion, this work demonstrates consequences for cellular metabolism associated with a loss of sacsin, which may be relevant to ARSACS.
线粒体功能障碍与神经疾病夏尔沃-萨格奈常染色体隐性痉挛性共济失调（ARSACS）的发病机制有关，但线粒体代谢究竟是如何受到影响的尚不清楚。因此，为了更好地了解由萨克斯蛋白（由SACS基因编码，该基因在ARSACS中发生突变）缺失引起的线粒体代谢变化，我们进行了基于质谱的示踪分析，同时追踪葡萄糖和谷氨酰胺中的碳。比较野生型和萨克斯基因敲除细胞系之间的代谢物谱发现，萨克斯蛋白缺陷细胞对有氧糖酵解的依赖性增加，乳酸增加和葡萄糖减少证明了这一点。此外，相对于对照，向神经元表型分化的萨克斯基因敲除细胞中三羧酸循环代谢物水平增加。我们还观察到在没有萨克斯蛋白的情况下，分化和未分化细胞中的谷氨酰胺分解途径受到破坏。总之，这项工作证明了与萨克斯蛋白缺失相关的细胞代谢后果，这可能与ARSACS有关。
