Trushina Eugenia, Trushin Sergey, Hasan Md Fayad
Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
Acta Pharm Sin B. 2022 Feb;12(2):483-495. doi: 10.1016/j.apsb.2021.11.003. Epub 2021 Nov 9.
Alzheimer's disease (AD), the most prominent form of dementia in the elderly, has no cure. Strategies focused on the reduction of amyloid beta or hyperphosphorylated Tau protein have largely failed in clinical trials. Novel therapeutic targets and strategies are urgently needed. Emerging data suggest that in response to environmental stress, mitochondria initiate an integrated stress response (ISR) shown to be beneficial for healthy aging and neuroprotection. Here, we review data that implicate mitochondrial electron transport complexes involved in oxidative phosphorylation as a hub for small molecule-targeted therapeutics that could induce beneficial mitochondrial ISR. Specifically, partial inhibition of mitochondrial complex I has been exploited as a novel strategy for multiple human conditions, including AD, with several small molecules being tested in clinical trials. We discuss current understanding of the molecular mechanisms involved in this counterintuitive approach. Since this strategy has also been shown to enhance health and life span, the development of safe and efficacious complex I inhibitors could promote healthy aging, delaying the onset of age-related neurodegenerative diseases.
阿尔茨海默病（AD）是老年人中最常见的痴呆形式，目前尚无治愈方法。专注于减少β-淀粉样蛋白或过度磷酸化 Tau 蛋白的策略在临床试验中大多失败。迫切需要新的治疗靶点和策略。新出现的数据表明，在应对环境压力时，线粒体启动了一种综合应激反应（ISR），已证明这种反应对健康衰老和神经保护有益。在这里，我们回顾了相关数据，这些数据表明参与氧化磷酸化的线粒体电子传递复合物是小分子靶向治疗的核心，这些治疗可能诱导有益的线粒体 ISR。具体而言，线粒体复合物 I 的部分抑制已被用作针对多种人类疾病（包括 AD）的新策略，有几种小分子正在临床试验中进行测试。我们讨论了目前对这种违反直觉方法所涉及分子机制的理解。由于该策略也已被证明可促进健康和延长寿命，开发安全有效的复合物 I 抑制剂可能会促进健康衰老，延缓与年龄相关的神经退行性疾病的发病。
