Ng Li Fang, Gruber Jan, Cheah Irwin K, Goo Chong Kiat, Cheong Wei Fun, Shui Guanghou, Sit Kim Ping, Wenk Markus R, Halliwell Barry
Department of Biochemistry, National University of Singapore, Singapore 117597, Singapore.
Department of Biochemistry, National University of Singapore, Singapore 117597, Singapore; Yale-NUS College, 6 College Avenue East, Singapore 138614, Singapore.
Free Radic Biol Med. 2014 Jun;71:390-401. doi: 10.1016/j.freeradbiomed.2014.03.003. Epub 2014 Mar 15.
β-Amyloid (Aβ)-induced toxicity and oxidative stress have been postulated to play critical roles in the pathogenic mechanism of Alzheimer disease (AD). We investigated the in vivo ability of a mitochondria-targeted antioxidant, MitoQ, to protect against Aβ-induced toxicity and oxidative stress in a Caenorhabditis elegans model overexpressing human Aβ. Impairment of electron transport chain (ETC) enzymatic activity and mitochondrial dysfunction are early features of AD. We show that MitoQ extends lifespan, delays Aβ-induced paralysis, ameliorates depletion of the mitochondrial lipid cardiolipin, and protects complexes IV and I of the ETC. Despite its protective effects on lifespan, healthspan, and ETC function, we find that MitoQ does not reduce DCFDA fluorescence, protein carbonyl levels or modulate steadystate ATP levels or oxygen consumption rate. Moreover, MitoQ does not attenuate mitochondrial DNA (mtDNA) oxidative damage. In agreement with its design, the protective effects of MitoQ appear to be targeted specifically to the mitochondrial membrane and our findings suggest that MitoQ may have therapeutic potential for Aβ- and oxidative stress-associated neurodegenerative disorders, particularly AD.
β-淀粉样蛋白（Aβ）诱导的毒性和氧化应激被认为在阿尔茨海默病（AD）的致病机制中起关键作用。我们研究了线粒体靶向抗氧化剂MitoQ在过表达人Aβ的秀丽隐杆线虫模型中，对Aβ诱导的毒性和氧化应激的体内保护能力。电子传递链（ETC）酶活性受损和线粒体功能障碍是AD的早期特征。我们发现MitoQ可延长寿命、延缓Aβ诱导的麻痹、改善线粒体脂质心磷脂的消耗，并保护ETC的复合物IV和I。尽管MitoQ对寿命、健康寿命和ETC功能有保护作用，但我们发现它不会降低DCFDA荧光、蛋白质羰基水平，也不会调节稳态ATP水平或氧消耗率。此外，MitoQ不会减轻线粒体DNA（mtDNA）的氧化损伤。与其设计一致，MitoQ的保护作用似乎特异性地靶向线粒体膜，我们的研究结果表明MitoQ可能对Aβ和氧化应激相关的神经退行性疾病，尤其是AD具有治疗潜力。
