Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Nature. 2013 May 23;497(7450):451-7. doi: 10.1038/nature12188.
Longevity is regulated by a network of closely linked metabolic systems. We used a combination of mouse population genetics and RNA interference in Caenorhabditis elegans to identify mitochondrial ribosomal protein S5 (Mrps5) and other mitochondrial ribosomal proteins as metabolic and longevity regulators. MRP knockdown triggers mitonuclear protein imbalance, reducing mitochondrial respiration and activating the mitochondrial unfolded protein response. Specific antibiotics targeting mitochondrial translation and ethidium bromide (which impairs mitochondrial DNA transcription) pharmacologically mimic mrp knockdown and extend worm lifespan by inducing mitonuclear protein imbalance, a stoichiometric imbalance between nuclear and mitochondrially encoded proteins. This mechanism was also conserved in mammalian cells. In addition, resveratrol and rapamycin, longevity compounds acting on different molecular targets, similarly induced mitonuclear protein imbalance, the mitochondrial unfolded protein response and lifespan extension in C. elegans. Collectively these data demonstrate that MRPs represent an evolutionarily conserved protein family that ties the mitochondrial ribosome and mitonuclear protein imbalance to the mitochondrial unfolded protein response, an overarching longevity pathway across many species.
长寿受代谢系统网络的紧密调节。我们使用了小鼠群体遗传学和 RNA 干扰相结合的方法，在秀丽隐杆线虫中鉴定出线粒体核糖体蛋白 S5（Mrps5）和其他线粒体核糖体蛋白是代谢和长寿的调节剂。MRP 敲低会引发线粒体核蛋白失衡，降低线粒体呼吸并激活线粒体未折叠蛋白反应。针对线粒体翻译的特定抗生素和溴化乙锭（可损害线粒体 DNA 转录）在药理学上模拟了 mrp 敲低，通过诱导线粒体核蛋白失衡（核编码蛋白和线粒体编码蛋白之间的化学计量失衡）来延长线虫寿命。这种机制在哺乳动物细胞中也得到了保守。此外，白藜芦醇和雷帕霉素，作用于不同分子靶点的长寿化合物，也以类似的方式诱导了线粒体核蛋白失衡、线粒体未折叠蛋白反应和秀丽隐杆线虫寿命的延长。这些数据共同表明，MRPs 代表了一个进化上保守的蛋白质家族，它将线粒体核糖体和线粒体核蛋白失衡与线粒体未折叠蛋白反应联系起来，这是一个跨越多个物种的普遍的长寿途径。
