Stöckl Petra, Zankl Christina, Hütter Eveline, Unterluggauer Hermann, Laun Peter, Heeren Gino, Bogengruber Edith, Herndler-Brandstetter Dietmar, Breitenbach Michael, Jansen-Dürr Pidder
Institute for Biomedical Aging Research, Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria.
Free Radic Biol Med. 2007 Sep 15;43(6):947-58. doi: 10.1016/j.freeradbiomed.2007.06.005. Epub 2007 Jun 13.
The mitochondrial theory of aging predicts that functional alterations in mitochondria leading to reactive oxygen species (ROS) production contribute to the aging process in most if not all species. Using cellular senescence as a model for human aging, we have recently reported partial uncoupling of the respiratory chain in senescent human fibroblasts. In the present communication, we address a potential cause-effect relationship between impaired mitochondrial coupling and premature senescence. Chronic exposure of human fibroblasts to the chemical uncoupler carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) led to a temporary, reversible uncoupling of oxidative phosphorylation. FCCP inhibited cell proliferation in a dose-dependent manner, and a significant proportion of the cells entered premature senescence within 12 days. Unexpectedly, chronic exposure of cells to FCCP led to a significant increase in ROS production, and the inhibitory effect of FCCP on cell proliferation was eliminated by the antioxidant N-acetyl-cysteine. However, antioxidant treatment did not prevent premature senescence, suggesting that a reduction in the level of oxidative phosphorylation contributes to phenotypical changes characteristic of senescent human fibroblasts. To assess whether this mechanism might be conserved in evolution, the influence of mitochondrial uncoupling on replicative life span of yeast cells was also addressed. Similar to our findings in human fibroblasts, partial uncoupling of oxidative phsophorylation in yeast cells led to a substantial decrease in the mother-cell-specific life span and a concomitant incrase in ROS, indicating that life span shortening by mild mitochondrial uncoupling may represent a "public" mechanism of aging.
衰老的线粒体理论预测，线粒体功能改变导致活性氧（ROS）产生，即便不是在所有物种中，也在大多数物种的衰老过程中发挥作用。我们最近以细胞衰老作为人类衰老的模型，报道了衰老的人类成纤维细胞呼吸链的部分解偶联。在本通讯中，我们探讨了线粒体偶联受损与早衰之间潜在的因果关系。将人类成纤维细胞长期暴露于化学解偶联剂羰基氰化物对三氟甲氧基苯腙（FCCP）会导致氧化磷酸化的暂时、可逆解偶联。FCCP以剂量依赖的方式抑制细胞增殖，并且相当一部分细胞在12天内进入早衰状态。出乎意料的是，细胞长期暴露于FCCP会导致ROS产生显著增加，并且抗氧化剂N - 乙酰半胱氨酸消除了FCCP对细胞增殖的抑制作用。然而，抗氧化剂处理并不能防止早衰，这表明氧化磷酸化水平的降低有助于衰老的人类成纤维细胞特征性的表型变化。为了评估这种机制在进化过程中是否保守，我们还研究了线粒体解偶联对酵母细胞复制寿命的影响。与我们在人类成纤维细胞中的发现相似，酵母细胞中氧化磷酸化的部分解偶联导致母细胞特异性寿命大幅缩短，同时ROS增加，这表明轻度线粒体解偶联导致的寿命缩短可能是一种“普遍”的衰老机制。
