Controlling mitochondrial bioenergetics with protein S-glutathionylation redox switches

线粒体是为哺乳动物细胞提供ATP所必需的，ATP是一种在细胞中进行有用“工作”的可用能量形式。ATP是由氧化磷酸化（OXPHOS）产生的，它将营养代谢释放的能量与ADP的磷酸化结合在一起。就像电线一样，从营养物质中释放出来的电子通过电子传导蛋白质复合物传递到链末端的分子氧（O2）。电子运动到O2是一个“有利的过程”，这意味着电子运动释放的能量可以被捕获用于生产ATP。不幸的是，OXPHOS不是一个完美的过程，有时电子可能会“泄漏”出链，并过早地与O2相互作用，产生活性氧（ROS）。大量的ROS是危险的，但需要少量的ROS来协调线粒体功能与细胞生理学的变化。事实上，ROS是驱动从细胞增殖到伤口愈合和心脏功能的基本细胞功能所必需的。真正令人惊讶的是，尽管有50年的研究，我们对线粒体如何控制ROS的形成只有初步的了解。考虑到它的二分法，破译线粒体如何调节产生多少ROS似乎非常重要。控制ROS的一种方法是使用内源性抗氧化剂，如谷胱甘肽（GSH），其在线粒体中以高水平存在。另一种方法是使用氧化还原开关，其可以控制电子从ROS产生位点的进入和退出。其中一个引起广泛关注的开关是蛋白质S-谷胱甘肽化（PGlu），它涉及GSH从酶中的物理附着和去除。PGlu反应是用于控制线粒体OXPHOS和ROS产生的有吸引力的开关，因为开关本身直接受GSH与ROS相互作用的量的影响。我的长期研究重点是提供PGlu在控制线粒体生物能量学和ROS产生中的功能的第一次深入评估。总体目标是提高我们对氧化还原开关如何控制重要信号分子ROS产生的理解。这包括确定哪些酶由PGlu控制，以及它对这些特定位点的OXPHOS和ROS形成的影响。这将是加拿大第一个剖析氧化还原开关在控制线粒体代谢和ROS形成中的功能的研究项目。它还首次提出了氧化还原开关在控制参与ROS形成的线粒体蛋白质组装中的功能。氧化还原生物学领域是一个充满令人兴奋和动态研究的新领域，因此预计这项研究计划的新奇将大大提高我们对氧化还原开关在控制线粒体和ROS信号传导中的作用的理解。

Mitochondria are required to furnish mammalian cells with ATP, a usable form of energy that performs useful “work” in a cell. ATP is generated by oxidative phosphorylation (OXPHOS) which couples the energy released from nutrient metabolism to the phosphorylation of ADP. Akin to an electrical wire, electrons liberated from nutrients are ferried through electron conducting protein complexes to molecular oxygen (O2) at the end of the chain. Electron movement to O2 is a “favorable process” which means that electron movement releases energy that can be trapped for the production of ATP. Unfortunately OXPHOS is not a perfect process and sometimes electrons can “leak” out of the chain and prematurely interact with O2 generating reactive oxygen species (ROS). ROS are dangerous at high quantities but low amounts are required to coordinate mitochondrial functions with changes in cell physiology. Indeed, ROS are required to drive basic cellular functions ranging from cell proliferation to wound healing and heart function. What is truly surprising is that despite 50 years of research we only have a rudimentary understanding of how mitochondria control ROS formation. Given its dichotomy, it would seem quite important to decipher how mitochondria modulate how much ROS is produced. One way to control ROS is with endogenous antioxidants like glutathione (GSH) which is found at high levels in mitochondria. Another way is with redox switches which can control the entry and exit of electrons from sites of ROS production. One switch that has gained a lot of attention is protein S-glutathionylation (PGlu) which involves the physical attachment and removal of GSH from enzymes. PGlu reactions are attractive switches for controlling mitochondrial OXPHOS and ROS production since the switches themselves are directly influenced by how much GSH is interacting with ROS. My long term research focus is to provide the first in depth assessment of the function of PGlu in controlling mitochondrial bioenergetics and ROS production. The overall goal is to enhance our understanding of how this redox switch controls the production of an important signaling molecule, ROS. This includes identifying which enzymes are controlled by PGlu and the impact it has on OXPHOS and ROS formation at these specific sites. This would be the first research program in Canada that dissects the function of redox switches in controlling mitochondrial metabolism and ROS formation. It also broaches for the first time the function of redox switches in controlling the assembly of mitochondrial proteins involved in ROS formation. The redox biology field is a new field filled with exciting and dynamic research and it is thus anticipated that the novelty of this research program will significantly advance our understanding of the role of redox switches in controlling mitochondria and ROS signaling.