Department of Pathology, Stanford University, Palo Alto, CA, United States of America.
Department of Immunology and Rheumatology, Stanford University, Palo Alto, CA, United States of America.
PLoS One. 2020 Oct 14;15(10):e0240517. doi: 10.1371/journal.pone.0240517. eCollection 2020.
Mitochondrial diseases are a clinically heterogenous group of disorders caused by respiratory chain dysfunction and associated with progressive, multi-systemic phenotype. There is no effective treatment or cure, and no FDA-approved drug for treating mitochondrial disease. To identify and characterize potential therapeutic compounds, we developed an in vitro screening assay and identified a group of direct AMP-activated protein kinase (AMPK) activators originally developed for the treatment of diabetes and metabolic syndrome. Unlike previously investigated AMPK agonists such as AICAR, these compounds allosterically activate AMPK in an AMP-independent manner, thereby increasing specificity and decreasing pleiotropic effects. The direct AMPK activator PT1 significantly improved mitochondrial function in assays of cellular respiration, energy status, and cellular redox. PT1 also protected against retinal degeneration in a mouse model of photoreceptor degeneration associated with mitochondrial dysfunction and oxidative stress, further supporting the therapeutic potential of AMP-independent AMPK agonists in the treatment of mitochondrial disease.
线粒体疾病是一组由呼吸链功能障碍引起的临床表现异质性疾病，与进行性多系统表型相关。目前尚无有效的治疗或治愈方法，也没有获得 FDA 批准用于治疗线粒体疾病的药物。为了鉴定和表征潜在的治疗化合物，我们开发了一种体外筛选测定法，并鉴定了一组最初用于治疗糖尿病和代谢综合征的直接 AMP 激活蛋白激酶 (AMPK) 激活剂。与以前研究过的 AMPK 激动剂如 AICAR 不同，这些化合物以 AMP 非依赖性方式别构激活 AMPK，从而提高了特异性并降低了多效性作用。直接 AMPK 激活剂 PT1 显著改善了细胞呼吸、能量状态和细胞氧化还原测定中的线粒体功能。PT1 还可防止与线粒体功能障碍和氧化应激相关的光感受器变性的小鼠模型中的视网膜变性，进一步支持 AMP 非依赖性 AMPK 激动剂在治疗线粒体疾病方面的治疗潜力。
