线粒体能量代谢的中心，也是细胞死亡调控中心和自由基产生的中心。线粒体呼吸链复合体II在电子传递、自由基产生和三羧酸循环中都发挥重要作用，与肿瘤的发生密切相关。有关复合体II参与电子传递和调节活性氧产生的分子细节及其在肿瘤发生中的作用还存在很大争论。我们建立了组织特异敲除SDHB的小鼠，为分析线粒体复合物II在自由基产生，线粒体能量代谢和信号调控提供了新的模型。初步结果发现肝脏特异敲除SDHB-/-小鼠出现明显的代谢和自由基产生异常。我们将深入分析SDHB肝脏特异敲除体系中复合体装配及活性变化，利用CoQ和线粒体特异的自由基清除剂干预，从而研究SDHB功能缺失情况下线粒体形态、功能变化和代谢相关信号途径的影响。并建立神经内中枢组织特异敲除的小鼠模型，分析其肿瘤发生的可能性。本申请从新的视角揭示复合体II在能量代谢、电子传递、活性氧产生和三羧酸循环中的关键作用及其在肿瘤发生中可能的作用。

Mitochondria is the powerhouse for cellular energy metabolism and they play central roles for cell death control and ROS generation. Mitochondrial complex II contains 4 subunits (SDHA,B,C,D) and meidates eletron tranfer and ROS production. Mutation of complex II genes causes paragangliomas, pheochromocytomas, renal cell carcinoma nad T cell acute leukemia. To address the underlying mechansim, we generate conditional knocked out mice to SDHB and SDHC. Conditional knockout of SDHB in liver has resulted abnormal liver functions. We will investigate how the assembly of complex II and other complex of respiration chain will be affected in the abesence of SDHB and SDHC. We will use CoQ and mitochondrial SOD mimetic to see if they can rescue mitochondrial functions. Conditional knockout of these genes in other tissues will be generated to investigate if deficiency of these genes cause cancers. Overall, our study will provide novel understanding on how complex II mediates the ROS porduction, how complex II works with other component of respiration chain for mitochondrial energy metabolisms and its potential role in tumorigenesis.