Role of mitochondrial permeability transition : from induction of cell death to control of energy homeostasis

点击翻译按钮获取中文摘要

The general research focus of this laboratory is on mitochondria, which are cellular organelles that play an important role in numerous key function including energy production, regulation of calcium equilibrium, production of reactive oxygen species and regulation of cell death. The present research proposal is divided in three parts each addressing distinct but complementary questions. The first part is focused on the mechanisms underlying the activation of cell death signalling in the atrophying skeletal muscle, a phenomenon which is currently believed to play a role in disuse. More specifically, we propose to clarify the role of the mitochondrial permeability transition pore (PTP), and of its regulating protein cyclophilin-D (CypD) in activating cell death. Our results will bring a direct answer to a currently debated question in this field. The second part builds on recent observations from our laboratory, and others, that in normal muscle, substantial functional differences exist between mitochondria from fast-twitch and slow-twitch muscle fibers. We propose to further establish the mechanism underlying the fiber type-specific regulation of the PTP, and determine whether coordinated changes in this regulation occur in response to molecular signals known to induce a shift in muscle fiber type. These results will provide novel insights on the specialization of mitochondria during skeletal muscle adaptation. Finally, the third part explores the novel and previously unexpected possibility that the PTP, which is mainly known for its role in cell death, plays a role in the regulation of energy metabolism and body weight. Indeed, mice that are resistant to PTP opening were recently shown to develop a pronounced adult-onset obesity. We propose to characterize this novel model and search for the underlying mechanisms in various tissues involved in whole body energy balance. This may lead to the identification of a novel means through which mitochondria regulate energy metabolism in tissues.