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.
