Mitochondrial disorders affect 1/5,000 and have no cure. Inducing mitochondrial biogenesis with bezafibrate improves mitochondrial function in animal models, but there are no comparable human studies. We performed an open-label observational experimental medicine study of six patients with mitochondrial myopathy caused by the m.3243A>G MTTL1 mutation. Our primary aim was to determine the effects of bezafibrate on mitochondrial metabolism, whilst providing preliminary evidence of safety and efficacy using biomarkers. The participants received 600-1,200 mg bezafibrate daily for 12 weeks. There were no clinically significant adverse events, and liver function was not affected. We detected a reduction in the number of complex IV-immunodeficient muscle fibres and improved cardiac function. However, this was accompanied by an increase in serum biomarkers of mitochondrial disease, including fibroblast growth factor 21 (FGF-21), growth and differentiation factor 15 (GDF-15), plus dysregulation of fatty acid and amino acid metabolism. Thus, although potentially beneficial in short term, inducing mitochondrial biogenesis with bezafibrate altered the metabolomic signature of mitochondrial disease, raising concerns about long-term sequelae.

中文翻译：

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苯扎贝特在线粒体疾病中的代谢作用。

线粒体疾病影响 1/5,000 并且无法治愈。用苯扎贝特诱导线粒体生物发生可改善动物模型中的线粒体功能，但没有可比的人体研究。我们对 6 名由 m.3243A>G MTTL1 突变引起的线粒体肌病患者进行了开放标签观察性实验医学研究。我们的主要目的是确定苯扎贝特对线粒体代谢的影响，同时使用生物标志物提供安全性和有效性的初步证据。参与者每天服用 600-1,200 毫克苯扎贝特，持续 12 周。没有临床上显着的不良事件，肝功能也没有受到影响。我们检测到复杂的 IV 免疫缺陷肌纤维数量减少，心脏功能得到改善。然而，这伴随着线粒体疾病血清生物标志物的增加，包括成纤维细胞生长因子 21 (FGF-21)、生长和分化因子 15 (GDF-15)，以及脂肪酸和氨基酸代谢的失调。因此，尽管在短期内可能有益，但用苯扎贝特诱导线粒体生物发生改变了线粒体疾病的代谢组学特征，引发了对长期后遗症的担忧。