Mechanisms of mitochondrial biogenesis in skeletal muscle

我的研究项目的长期目标是了解肌肉在适应收缩活动增加和减少（即运动）过程中线粒体生物发生的分子途径。生物发生途径的生理结果是在肌肉内形成一个健康的细胞器池，负责ATP的产生、细胞凋亡、活性氧（ROS）的产生以及细胞器向细胞核发出信号以调节基因表达。在过去的5年里，我们的nserc支持的研究项目非常成功地识别了参与运动诱导的线粒体转换激活的重要蛋白质，以及量化线粒体动力学，以及运动诱导的溶酶体在肌肉中的生物发生的惊人规模。这些发现为我们继续关注运动信号到细胞核的新型分子换能器，导致线粒体适应运动的事件，以及使用运动作为诱导刺激的肌肉内细胞器（线粒体-溶酶体-核）通信的动态性质奠定了基础。利用多种成熟的体内和细胞培养方法来产生急性和慢性运动，我们的新目标是研究：1)Nrf2蛋白作为细胞器生物发生和线粒体自噬平衡的调节因子的新功能；2)肌管内线粒体运动的显著变化及其与收缩活动诱导的细胞器动力学的关系；3) UPRmt对运动应激的激活、对细胞器蛋白质输入的调节以及激活转录因子-5 （ATF5）对线粒体和细胞核之间信号的控制之间的相互作用；4)独特的磷脂心磷脂在慢性肌肉使用和废用介导的周转过程中决定细胞器功能和蛋白质输入的作用。这些过程将使用生化和分子生物学技术进行评估，以及生理分析来评估肌肉和细胞器呼吸和活性氧的产生。这项工作的意义在于，它继续使用从分子到全身水平的多种方法，对运动诱导的线粒体生物发生进行长期、全面的分析，以评估细胞器组装和通信的机制，以及它们在哺乳动物肌肉中的功能后果。所获得的结果对细胞器合成的基本机制、我们对氧化代谢的理解以及线粒体在细胞健康、疾病和死亡中的功能具有更广泛的适用性。

The long-term objective of my research program is to understand the molecular pathways of mitochondrial biogenesis in muscle during adaptations to increases and decreases in contractile activity (i.e. exercise). The physiological consequences of the biogenesis pathway is the formation of a healthy organelle pool within muscle, responsible for ATP production, apoptosis, the generation of reactive oxygen species (ROS), and organelle signaling to the nucleus to regulate gene expression. Our NSERC-supported research program over the last 5 years was very successful in identifying important proteins involved in the exercise-induced activation of mitochondrial turnover, as well as quantifying mitochondrial dynamics, and the surprising magnitude of exercise-induced lysosome biogenesis in muscle. These discoveries set the stage for us to continue to focus on novel molecular transducers of exercise signals to the nucleus, the events that lead to mitochondrial adaptations in response to exercise, as well as the dynamic nature of organelle (mitochondrial-lysosome-nucleus) communication within muscle using exercise as an inducing stimulus. Using a variety of well-established in vivo and cell culture approaches to produce acute and chronic exercise, our new Objectives are to investigate: 1) a novel function of the protein Nrf2 as a regulator of the balance between organelle biogenesis and mitophagy; 2) the remarkable changes in mitochondrial motility within myotubes, and the relationship of these movements to organelle dynamics induced by contractile activity; 3) the interaction between the activation of the UPRmt to exercise stress, the regulation of protein import into the organelle, and the control exerted by Activating Transcription Factor-5 (ATF5) in determining signals between mitochondria and the nucleus, and 4) the role of the unique phospholipid cardiolipin in determining organelle function and protein import during turnover mediated by chronic muscle use and disuse. These processes will be evaluated using biochemical and molecular biology techniques, along with physiological analyses to assess muscle and organelle respiration and ROS production. The significance of this work is that it continues to represent a long-term, comprehensive analysis of exercise-induced mitochondrial biogenesis using multiple approaches, from the molecular to whole body level, to evaluate the mechanisms of organelle assembly and communication, as well as their functional consequences in mammalian muscle. The results obtained have wider applicability to the basic mechanisms of organelle synthesis, our understanding of oxidative metabolism, as well as the function of mitochondria in cellular health, disease and death.