GENETIC APPROACHES TO MITOCHONDRIAL VDAC FUNCTION

描述：电压依赖性阴离子通道（VDAC）是小的外部通道， 线粒体膜蛋白在所有真核生物中发现。 VDAC位于 与腺嘌呤核苷酸转运蛋白密切相关， 结合几种激酶，这些激酶以可溶性胞质形式和 线粒体膜结合形式。 已知结合VDAC的激酶包括 己糖激酶、葡糖激酶、甘油激酶和线粒体肌酸激酶。 这组激酶在多种代谢功能中很重要 包括糖酵解、磷酸肌酸回路、甘油三酯代谢， 和葡萄糖稳态。 与VDAC的结合是代谢性的， 以组织特异性的方式发育调节，并在 转化细胞系。 VDAC也是外设的一个组件 苯二氮卓受体，其参与类固醇生成。 之甚少 已知VDAC在哺乳动物中的生理作用，尽管最近 报告一个儿童线粒体肌病与缺乏 VDAC 1表明在肌肉能量经济中的重要作用。 我们假设单个VDAC亚型结合特异性激酶， 调节特定的代谢途径。 特别是，假设 VDAC有助于控制肌肉中的磷酸肌酸回路， 通过调节磷酸肌酸和腺嘌呤核苷酸的流量 穿过线粒体外膜 首席研究员的实验室 分离出三种不同的小鼠VDAC基因， 无论是在培养的细胞系还是小鼠中。 该项目的目标是使用 这些突变细胞和动物来验证这些假设。 更准确地说， 线粒体呼吸功能，外膜对ADP的通透性，以及 将在细胞中研究外膜电生理特性 线，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是否发挥 在代谢稳态中的重要作用，ii）存在功能冗余， iii）VDAC是人类肌病的潜在候选基因，和 VDAC缺陷型小鼠是用于治疗某些先天性免疫缺陷的模型。 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.