GENETIC APPROACHES TO MITOCHONDRIAL VDAC FUNCTION

描述：电压依赖的阴离子通道(VDAC)很小 存在于所有真核生物中的线粒体膜蛋白。VDAC位于 与腺嘌呤核苷酸转运体紧密结合，并直接 结合几种既以可溶性胞浆形式存在又以一种 线粒体膜结合型。已知的与VDAC结合的激酶包括 己糖、葡糖、甘油和线粒体肌酸激酶。 这组激酶在多种代谢功能中都很重要。 包括糖酵解，磷酸肌酸循环，甘油三酯代谢， 和葡萄糖动态平衡。与VDAC的结合是通过代谢和 以组织特有的方式发育调节，并在 转化的细胞系。VDAC也是外围设备的组件 参与类固醇合成的苯二氮卓类受体。小才是 已知VDAC在哺乳动物中的生理作用，尽管最近 1例儿童线粒体肌病伴缺乏症的报告 VDACl提示在肌肉能量经济中起着重要作用。 我们假设单个VDAC亚型结合特定的激酶，从而 调节特定的代谢途径。特别是，它是假设的 VDAC在肌肉磷酸肌酸环路调控中的作用 通过调节磷酸肌酸和腺嘌呤核苷酸的流量来调节组织 穿过线粒体膜外壁。首席调查员实验室 已经分离出三个不同的小鼠VDAC基因，并扰乱了这三个基因 在培养的细胞系和小鼠中都是如此。该项目的目标是使用 这些突变的细胞和动物来检验这些假设。更准确地说， 线粒体呼吸功能、外膜对ADP的通透性 外膜的电生理特性将在细胞中进行研究 线条，而骨骼肌的结构和功能将在 突变小鼠品系以确定VDAC的相对重要性 在体内发挥作用。这些研究将确定i)VDAC是否扮演着 在代谢动态平衡中的重要作用，ii)存在功能冗余， Iii)VDAC是人类肌病的潜在候选基因，以及 VDAC缺陷小鼠是治疗某些先天性心脏病的模型 肌病。

DESCRIPTION: Voltage dependent anion channels (VDACs) are small outer mitochondrial membrane proteins found in all eukaryotes. VDACs are found in close association with the Adenine Nucleotide Translocator, and directly bind several kinases that exist both in a soluble cytosolic form and a mitochondrial membrane-bound form. The kinases known to bind VDACs include hexokinase, glucokinase, glycerol kinase, and mitochondrial creatine kinase. This group of kinases is important in a variety of metabolic functions including glycolysis, the phosphocreatine circuit, triglyceride metabolism, and glucose homeostasis. Binding to VDACs is metabolically and developmentally regulated in a tissue-specific fashion, and is enhanced in transformed cell lines. VDACs are also a component of the peripheral benzodiazepine receptor, which is involved in steroidogenesis. Little is known about the physiologic role of VDACs in mammals, although a recent report of a child with a mitochondrial myopathy associated with absence of VDACl suggests an important role in muscle energy economy. We hypothesize that individual VDAC isoforms bind specific kinases, thereby regulating specific metabolic pathways. In particular, it is hypothesized that VDACs contribute to the control the phosphocreatine circuit in muscle tissue by regulating the flux of phosphocreatine and adenine nucleotides across the outer mitochondrial membrane. The principal investigator's lab has isolated three distinct mouse VDAC genes and disrupted all three genes both in cultured cell lines and mice. The goal of this project is to use these mutant cells and animals to test these hypotheses. More precisely, mitochondrial respiratory function, outer membrane permeability to ADP, and outer membrane electrophysiological properties will be studied in the cell lines, while skeletal muscle structure and function will be examined in mutant mouse strains in order to determine the relative importance of VDAC function in vivo. These studies will identify whether i) VDACs play a significant role in metabolic homeostasis, ii) functional redundancy exists, iii) VDACs are potential candidate genes for human myopathies, and iiii) VDAC deficient mice are models for the treatment of certain congenital myopathies.