Neufeld-Cohen Adi, Robles Maria S, Aviram Rona, Manella Gal, Adamovich Yaarit, Ladeuix Benjamin, Nir Dana, Rousso-Noori Liat, Kuperman Yael, Golik Marina, Mann Matthias, Asher Gad
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 7610001, Israel;
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried 82152, Germany;
Proc Natl Acad Sci U S A. 2016 Mar 22;113(12):E1673-82. doi: 10.1073/pnas.1519650113. Epub 2016 Feb 9.
Mitochondria are major suppliers of cellular energy through nutrients oxidation. Little is known about the mechanisms that enable mitochondria to cope with changes in nutrient supply and energy demand that naturally occur throughout the day. To address this question, we applied MS-based quantitative proteomics on isolated mitochondria from mice killed throughout the day and identified extensive oscillations in the mitochondrial proteome. Remarkably, the majority of cycling mitochondrial proteins peaked during the early light phase. We found that rate-limiting mitochondrial enzymes that process lipids and carbohydrates accumulate in a diurnal manner and are dependent on the clock proteins PER1/2. In this conjuncture, we uncovered daily oscillations in mitochondrial respiration that peak during different times of the day in response to different nutrients. Notably, the diurnal regulation of mitochondrial respiration was blunted in mice lacking PER1/2 or on a high-fat diet. We propose that PERIOD proteins optimize mitochondrial metabolism to daily changes in energy supply/demand and thereby, serve as a rheostat for mitochondrial nutrient utilization.
线粒体是通过营养物质氧化提供细胞能量的主要细胞器。关于线粒体如何应对一天中自然发生的营养供应和能量需求变化的机制，我们所知甚少。为了解决这个问题，我们对全天不同时间处死的小鼠分离出的线粒体进行了基于质谱的定量蛋白质组学研究，并确定了线粒体蛋白质组存在广泛的振荡。值得注意的是，大多数循环线粒体蛋白在清晨光照阶段达到峰值。我们发现，处理脂质和碳水化合物的限速线粒体酶以昼夜节律的方式积累，并且依赖于生物钟蛋白PER1/2。在此情况下，我们发现线粒体呼吸存在每日振荡，在一天中的不同时间，根据不同的营养物质达到峰值。值得注意的是，在缺乏PER1/2的小鼠或高脂饮食的小鼠中，线粒体呼吸的昼夜调节减弱。我们提出，周期蛋白可根据能量供应/需求的每日变化优化线粒体代谢，从而作为线粒体营养利用的变阻器。
