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

该实验室的一般研究重点是线粒体，线粒体是在许多关键功能中发挥重要作用的细胞器，包括能量产生，钙平衡调节，活性氧的产生和细胞死亡的调节。本研究建议分为三个部分，每个部分处理不同但互补的问题。第一部分集中在萎缩的骨骼肌中细胞死亡信号的激活的机制上，目前认为这种现象在废用中起作用。更具体地说，我们建议澄清线粒体通透性转换孔（PTP），其调节蛋白亲环素-D（CypD）在激活细胞死亡的作用。我们的研究结果将为这一领域目前争论的问题带来直接的答案。第二部分建立在我们实验室和其他人最近的观察基础上，即在正常肌肉中，快肌纤维和慢肌纤维的线粒体之间存在着实质性的功能差异。我们建议进一步建立PTP的纤维类型特异性调节的机制，并确定这种调节是否发生协调变化，以响应已知诱导肌纤维类型转变的分子信号。这些结果将为骨骼肌适应过程中线粒体的特化提供新的见解。最后，第三部分探讨了新的和以前意想不到的可能性，即PTP，这主要是已知的细胞死亡中的作用，在能量代谢和体重的调节中发挥作用。事实上，最近显示对PTP开放有抵抗力的小鼠发展出明显的成年型肥胖症。我们建议描述这种新的模型，并在参与全身能量平衡的各种组织中寻找潜在的机制。这可能导致一种新的手段，通过线粒体调节组织中的能量代谢的鉴定。

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.