Abstract：
Mitochondrial diseases represent one of the most common groups of genetic diseases. With a prevalence greater than 1 in 5000 adults, such diseases still lack effective treatment. Current therapies are purely palliative and, in most cases, insufficient. Novel approaches to compensate and, if possible, revert mitochondrial dysfunction must be developed.
In this study, we tackled the issue using as a model fibroblasts from a patient bearing a mutation in the GFM1 gene, which is involved in mitochondrial protein synthesis. Mutant GFM1 fibroblasts could not survive in galactose restrictive medium for more than 3 days, making them the perfect screening platform to test several compounds. Tetracycline enabled mutant GFM1 fibroblasts survival under nutritional stress. Here we demonstrate that tetracycline upregulates the mitochondrial Unfolded Protein Response (UPRmt), a compensatory pathway regulating mitochondrial proteostasis. We additionally report that activation of UPRmt improves mutant GFM1 cellular bioenergetics and partially restores mitochondrial protein expression.
Overall, we provide compelling evidence to propose the activation of intrinsic cellular compensatory mechanisms as promising therapeutic strategy for mitochondrial diseases.
In this study, we tackled the issue using as a model fibroblasts from a patient bearing a mutation in the GFM1 gene, which is involved in mitochondrial protein synthesis. Mutant GFM1 fibroblasts could not survive in galactose restrictive medium for more than 3 days, making them the perfect screening platform to test several compounds. Tetracycline enabled mutant GFM1 fibroblasts survival under nutritional stress. Here we demonstrate that tetracycline upregulates the mitochondrial Unfolded Protein Response (UPRmt), a compensatory pathway regulating mitochondrial proteostasis. We additionally report that activation of UPRmt improves mutant GFM1 cellular bioenergetics and partially restores mitochondrial protein expression.
Overall, we provide compelling evidence to propose the activation of intrinsic cellular compensatory mechanisms as promising therapeutic strategy for mitochondrial diseases.
摘要：
线粒体疾病是最常见的遗传疾病之一。患病率超过5000名成年人中的1名，这些疾病仍然缺乏有效的治疗方法。目前的疗法纯粹是姑息治疗，在大多数情况下,不足。补偿和补偿的新方法，如果可能,必须开发恢复线粒体功能障碍。
在这项研究中,我们使用来自GFM1基因突变患者的成纤维细胞作为模型来解决这个问题，参与线粒体蛋白质合成。突变体GFM1成纤维细胞不能在半乳糖限制性培养基中存活超过3天,使它们成为测试几种化合物的完美筛选平台。四环素使突变GFM1成纤维细胞在营养应激下存活。在这里，我们证明四环素上调线粒体未折叠蛋白反应（UPRmt），调节线粒体蛋白质平衡的补偿途径。我们还报告说，UPRmt的激活改善了突变体GFM1细胞生物能学，并部分恢复了线粒体蛋白的表达。
总的来说，我们提供了令人信服的证据,提出激活内在细胞代偿机制作为线粒体疾病的有希望的治疗策略.
在这项研究中,我们使用来自GFM1基因突变患者的成纤维细胞作为模型来解决这个问题，参与线粒体蛋白质合成。突变体GFM1成纤维细胞不能在半乳糖限制性培养基中存活超过3天,使它们成为测试几种化合物的完美筛选平台。四环素使突变GFM1成纤维细胞在营养应激下存活。在这里，我们证明四环素上调线粒体未折叠蛋白反应（UPRmt），调节线粒体蛋白质平衡的补偿途径。我们还报告说，UPRmt的激活改善了突变体GFM1细胞生物能学，并部分恢复了线粒体蛋白的表达。
总的来说，我们提供了令人信服的证据,提出激活内在细胞代偿机制作为线粒体疾病的有希望的治疗策略.
