Genetic strategies for dissecting mammalian and Drosophila voltage-dependent anion channel functions
Genetic strategies for dissecting mammalian and Drosophila voltage-dependent anion channel functions
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DOI：
10.1007/s10863-008-9146-x
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发表时间：
2008-06-01
影响因子：
3
通讯作者：
Graham, Brett H.
中科院分区：
文献类型：
--
作者：
Craigen, William J.;Graham, Brett H.
电压依赖性阴离子通道（VDAC），也称为线粒体孔蛋白，是在所有真核生物中发现的线粒体外膜的小孔形成蛋白家族。VDAC被认为在调节胞质和线粒体区室之间的代谢物通量、通过与胞质激酶的相互作用在总体能量代谢中发挥重要作用，并且在程序性细胞死亡（细胞凋亡）中发挥有争议的作用。哺乳动物基因组包含三个VDAC基因座，分别称为Vdac1、Vdac2和Vdac3，这就提出了一个问题，即每个亚型可能执行什么功能。基于小鼠VDAC在酵母中的表达研究，可以鉴定出生物物理差异，但这些差异的生理学意义仍不清楚。缺乏一种或多种VDAC同种型的"敲除"细胞系和小鼠的产生导致了不同表型的表征，其提供了对必须在复杂生理系统的背景下解释的功能的不同见解。男性生殖、中枢神经系统和葡萄糖稳态的功能已经确定，需要更深入和更机械的检查。最近对果蝇基因组序列的注释发现了另外三个基因（CG17137、CG17139、CG17140），它们与先前描述的编码果蝇VDAC的基因孔蛋白同源。黑腹菌对这些新型VDAC的分子分析揭示了基因组织和表达的复杂模式。与其他昆虫VDAC同源物的序列比较表明，该基因家族通过复制和分化的机制从祖先VDAC基因在辐射的果蝇属。可以发现与小鼠VDAC突变体的惊人相似之处，其强调在长进化时间框架内的功能保守性。
Voltage-dependent anion channels (VDACs), also known as mitochondrial porins, are a family of small pore-forming proteins of the mitochondrial outer membrane that are found in all eukaryotes. VDACs are thought to play important roles in the regulated flux of metabolites between the cytosolic and mitochondrial compartments, in overall energy metabolism via interactions with cytosolic kinases, and a debated role in programmed cell death (apoptosis). The mammalian genome contains three VDAC loci termed Vdac1, Vdac2, and Vdac3, raising the question as to what function each isoform may be performing. Based upon expression studies of the mouse VDACs in yeast, biophysical differences can be identified but the physiologic significance of these differences remains unclear. Creation of "knockout" cell lines and mice that lack one or more VDAC isoforms has led to the characterization of distinct phenotypes that provide a different set of insights into function which must be interpreted in the context of complex physiologic systems. Functions in male reproduction, the central nervous system and glucose homeostasis have been identified and require a deeper and more mechanistic examination. Annotation of the genome sequence of Drosophila melanogaster has recently revealed three additional genes (CG17137, CG17139, CG17140) with homology to porin, the previously described gene that encodes the VDAC of D. melanogaster. Molecular analysis of these novel VDACs has revealed a complex pattern of gene organization and expression. Sequence comparisons with other insect VDAC homologs suggest that this gene family evolved through a mechanism of duplication and divergence from an ancestral VDAC gene during the radiation of the genus Drosophila. Striking similarities to mouse VDAC mutants can be found that emphasize the conservation of function over a long evolutionary time frame.