Lithocholic bile acid accumulated in yeast mitochondria orchestrates a development of an anti-aging cellular pattern by causing age-related changes in cellular proteome
Lithocholic bile acid accumulated in yeast mitochondria orchestrates a development of an anti-aging cellular pattern by causing age-related changes in cellular proteome
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DOI：
10.1080/15384101.2015.1026493
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发表时间：
2015-06-03
期刊：
影响因子：
4.3
通讯作者：
Titorenko, Vladimir I.
中科院分区：
文献类型：
--
作者：
Beach, Adam;Richard, Vincent R.;Titorenko, Vladimir I.
我们之前已经发现，外源添加石胆胆汁酸（LCA）可以延长酿酒酵母的寿命，在线粒体中积累并改变线粒体膜脂质组。在这里，我们使用定量质谱法来证明 LCA 改变了许多线粒体蛋白质以及线粒体外细胞位置中的许多蛋白质水平变化的与年龄相关的动态变化。这些蛋白质属于 2 个调节子，每个调节子由不同的线粒体功能障碍调节。我们将它们称为部分线粒体功能障碍调节子和氧化应激调节子。我们发现构成这些调节子的蛋白质 (1) 可以分为几个“簇”，每个“簇”表示一种不同类型的部分线粒体功能障碍，引发由一组离散转录因子介导的不同信号通路； (2) 表现出 3 种不同的细胞水平变化的年龄相关动态模式； (3) 由其表达受转录因子 Rtg1p/Rtg2p/Rtg3p、Sfp1p、Aft1p、Yap1p、Msn2p/Msn4p、Skn7p 和 Hog1p 调节的基因编码，每个因子对于 LCA 延长寿命都是必需的。我们的研究结果表明，LCA驱动的线粒体脂质组变化改变了线粒体蛋白质组和功能，从而使线粒体能够作为信号细胞器，为许多决定寿命的核基因协调建立抗衰老转录程序。基于这些发现，我们提出了一个模型，用于解释按时间顺序老化的酵母在生命早期和晚期这种由 LCA 驱动的变化如何导致抗衰老细胞模式的逐步发展及其在整个生命周期中的维持。
We have previously revealed that exogenously added lithocholic bile acid (LCA) extends the chronological lifespan of the yeast Saccharomyces cerevisiae, accumulates in mitochondria and alters mitochondrial membrane lipidome. Here, we use quantitative mass spectrometry to show that LCA alters the age-related dynamics of changes in levels of many mitochondrial proteins, as well as numerous proteins in cellular locations outside of mitochondria. These proteins belong to 2 regulons, each modulated by a different mitochondrial dysfunction; we call them a partial mitochondrial dysfunction regulon and an oxidative stress regulon. We found that proteins constituting these regulons (1) can be divided into several "clusters", each of which denotes a distinct type of partial mitochondrial dysfunction that elicits a different signaling pathway mediated by a discrete set of transcription factors; (2) exhibit 3 different patterns of the age-related dynamics of changes in their cellular levels; and (3) are encoded by genes whose expression is regulated by the transcription factors Rtg1p/Rtg2p/Rtg3p, Sfp1p, Aft1p, Yap1p, Msn2p/Msn4p, Skn7p and Hog1p, each of which is essential for longevity extension by LCA. Our findings suggest that LCA-driven changes in mitochondrial lipidome alter mitochondrial proteome and functionality, thereby enabling mitochondria to operate as signaling organelles that orchestrate an establishment of an anti-aging transcriptional program for many longevity-defining nuclear genes. Based on these findings, we propose a model for how such LCA-driven changes early and late in life of chronologically aging yeast cause a stepwise development of an anti-aging cellular pattern and its maintenance throughout lifespan.