Mechanisms of mitochondrial biogenesis in skeletal muscle

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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.