Previously we showed that dimethyl fumarate (DMF) dose-dependently increased mitochondrial gene expression and function in cells and might be considered as a therapeutic for inherited mitochondrial disease, including Friedreich’s ataxia (FA). Here we tested DMF’s ability to dose-dependently increase mitochondrial function, mitochondrial gene expression (frataxin and cytochrome oxidase protein) and mitochondrial copy number in C57BL6 wild-type mice and the FXNKD mouse model of FA. We first dosed DMF at 0–320 mg/kg in C57BL6 mice and observed significant toxicity above 160 mg/kg orally, defining the maximum tolerated dose. Oral dosing of C57BL6 mice in the range 0–160 mg/kg identified a maximum increase in aconitase activity and mitochondrial gene expression in brain and quadriceps at 110 mg/kg DMF, thus defining the maximum effective dose (MED). The MED of DMF in mice overlaps the currently approved human-equivalent doses of DMF prescribed for multiple sclerosis (480 mg/day) and psoriasis (720 mg/day). In the FXNKD mouse model of FA, which has a doxycycline-induced deficit of frataxin protein, we observed significant decreases of multiple mitochondrial parameters, including deficits in brain mitochondrial Complex 2, Complex 4 and aconitase activity, supporting the idea that frataxin deficiency reduces mitochondrial gene expression, mitochondrial functions and biogenesis. About 110 mg/kg of oral DMF rescued these enzyme activities in brain and rescued frataxin and cytochrome oxidase expression in brain, cerebellum and quadriceps muscle of the FXNKD mouse model. Taken together, these results support the idea of using fumarate-based molecules to treat FA or other mitochondrial diseases.

中文翻译：

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富马酸二甲酯剂量依赖性地增加弗里德赖希共济失调模型小鼠肌肉和大脑中的线粒体基因表达和功能

以前我们发现富马酸二甲酯 (DMF) 剂量依赖性地增加细胞中线粒体基因的表达和功能，并且可能被认为是遗传性线粒体疾病的治疗剂，包括弗里德赖希的共济失调 (FA)。在这里，我们测试了 DMF 在 C57BL6 野生型小鼠和 FA 的 FXNKD 小鼠模型中剂量依赖性地增加线粒体功能、线粒体基因表达（frataxin 和细胞色素氧化酶蛋白）和线粒体拷贝数的能力。我们首先在 C57BL6 小鼠中以 0-320 mg/kg 的剂量给药 DMF，并观察到口服超过 160 mg/kg 的显着毒性，确定了最大耐受剂量。C57BL6 小鼠在 0-160 mg/kg 范围内的口服剂量确定了 110 mg/kg DMF 时脑和股四头肌中乌头酸酶活性和线粒体基因表达的最大增加，从而确定了最大有效剂量 (MED)。小鼠中 DMF 的 MED 与目前批准的用于多发性硬化症（480 毫克/天）和银屑病（720 毫克/天）的人体等效 DMF 剂量重叠。在 FA 的 FXNKD 小鼠模型中，多西环素诱导的 frataxin 蛋白缺乏，我们观察到多个线粒体参数显着降低，包括脑线粒体复合物 2、复合物 4 和乌头酸酶活性的缺陷，支持了 frataxin 缺乏减少线粒体的观点。基因表达、线粒体功能和生物发生。大约 110 mg/kg 的口服 DMF 在 FXNKD 小鼠模型的大脑、小脑和股四头肌中拯救了这些酶活性，并拯救了 frataxin 和细胞色素氧化酶在大脑、小脑和股四头肌中的表达。总之，这些结果支持使用基于富马酸盐的分子治疗 FA 或其他线粒体疾病的想法。