Regulation of mitochondrial metabolism by the phosphorylation system and the complex IV and its impact on oxidative stress

心脏和骨骼肌收缩所需的大部分能量来自氧化磷酸化（OXPHOS），这是一个发生在线粒体内膜中的过程。OXPHOS将电子传递系统（ETS）中的电子转移与质子在膜间空间中的移动相耦合。形成的质子梯度在两个线粒体膜之间积累，并被磷酸化系统利用以ATP的形式产生能量。所产生的能量不仅取决于ETS的复合物I至IV之间的电子传递效率，还取决于磷酸化系统将质子梯度转化为能量的能力。例如，以前的研究表明，磷酸化系统对人类心脏和骨骼肌中的OXPHOS具有很强的控制作用，而这种特殊的特性并不与常用的动物模型（如小鼠和大鼠）共享。拟议的计划研究线粒体代谢调节机制的种内和种间差异以及调节机制与氧化应激之间的联系。了解物种和细胞条件之间线粒体代谢调节的差异及其对氧化应激的后果是至关重要的。如果一个一般的条件或突变修改ETS复合物，影响可能是轻微的，如果线粒体主要由磷酸化系统调节，或戏剧性的，如果物种或组织具有线粒体主要由ETS复合物控制。确定线粒体代谢调节位点的物种差异以及对氧化应激的影响对于适当解释线粒体功能与衰老或肌肉能量缺乏之间的联系至关重要。

A large fraction of energy needed for heart and skeletal muscle contraction comes from oxidative phosphorylation (OXPHOS), a process that takes place in the inner mitochondrial membrane. OXPHOS couple the transfer of electrons in the electron transport system (ETS) to the movement of protons in the intermembrane space. The proton gradient formed is accumulated between the two mitochondrial membranes and is utilized by the phosphorylation system to produce energy in the form of ATP. The energy produced depends not only from the efficiency of electron transport between the complexes I to IV of the ETS but also of the ability of the phosphorylation system to convert the proton gradient into energy. For instance, previous studies showed that the phosphorylation system exert a strong control on OXPHOS in the human heart and skeletal muscle, whereas this particular characteristic is not shared with commonly used animal models such as mice and rats.**The proposed program studies the intra and interspecific variation in the regulatory mechanisms of mitochondrial metabolism and the link between the regulatory mechanisms and the oxidative stress. Understanding the difference in regulation of mitochondrial metabolism between species and cellular conditions and their consequences on oxidative stress is essential. If a general condition or a mutation modifies an ETS complex, the effect could be either minor if the mitochondria are regulated principally by the phosphorylation system, or dramatic if the species or the tissue has mitochondria controlled mainly by the ETS complexes. Identifying the species difference in the site of regulation of mitochondrial metabolism and the impact on oxidative stress is essential for an appropriate interpretation of the link between mitochondrial function and aging or muscle energy deficiencies.