PDF(Pubmed)
Abstract：
Primary mitochondrial diseases result from mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) genes, encoding proteins crucial for mitochondrial structure or function. Given that few disease-specific therapies are available for mitochondrial diseases, novel treatments to reverse mitochondrial dysfunction are necessary. In this work, we explored new therapeutic options in mitochondrial diseases using fibroblasts and induced neurons derived from patients with mutations in the GFM1 gene. This gene encodes the essential mitochondrial translation elongation factor G1 involved in mitochondrial protein synthesis. Due to the severe mitochondrial defect, mutant GFM1 fibroblasts cannot survive in galactose medium, making them an ideal screening model to test the effectiveness of pharmacological compounds. We found that the combination of polydatin and nicotinamide enabled the survival of mutant GFM1 fibroblasts in stress medium. We also demonstrated that polydatin and nicotinamide upregulated the mitochondrial Unfolded Protein Response (mtUPR), especially the SIRT3 pathway. Activation of mtUPR partially restored mitochondrial protein synthesis and expression, as well as improved cellular bioenergetics. Furthermore, we confirmed the positive effect of the treatment in GFM1 mutant induced neurons obtained by direct reprogramming from patient fibroblasts. Overall, we provide compelling evidence that mtUPR activation is a promising therapeutic strategy for GFM1 mutations.
摘要：
原发性线粒体疾病是由核DNA（nDNA）或线粒体DNA（mtDNA）基因突变引起的，编码对线粒体结构或功能至关重要的蛋白质。鉴于针对线粒体疾病的疾病特异性疗法很少，逆转线粒体功能障碍的新疗法是必要的。在这项工作中,我们探索了使用GFM1基因突变患者的成纤维细胞和诱导神经元治疗线粒体疾病的新选择.该基因编码参与线粒体蛋白质合成的必需线粒体翻译延伸因子G1。由于严重的线粒体缺陷,突变GFM1成纤维细胞不能在半乳糖培养基中存活，使它们成为测试药理化合物有效性的理想筛选模型。我们发现虎杖苷和烟酰胺的组合能够使突变GFM1成纤维细胞在应激介质中存活。我们还证明了虎杖苷和烟酰胺上调线粒体未折叠蛋白反应（mtUPR），尤其是SIRT3途径。mtUPR激活部分恢复线粒体蛋白合成和表达，以及改进的细胞生物能学。此外，我们证实了该治疗在通过直接重编程从患者成纤维细胞获得的GFM1突变诱导的神经元中的积极作用.总的来说,我们提供了令人信服的证据,证明mtUPR激活是GFM1突变的有前景的治疗策略.
