Genetic strategies for dissecting mammalian and Drosophila voltage-dependent anion channel functions |
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Authors: | William J Craigen Brett H Graham |
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Institution: | (1) Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA;(2) Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA |
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Abstract: | 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. |
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Keywords: | Voltage-dependent Anion Channel Porin Mitochondria Drosophila Animal models |
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