Preliminary Characterization of VDAC3, an Elusive Member of the Outer Mitochondrial Membrane Pore Family.

The VDAC (Voltage Dependent Anion selective Channel) family of proteins is composed of three evolutionary related isoforms in vertebrates [1-2]. Despite the sequence similarity, the functional data existing nowadays point to different functions for them. The isoforms are expressed at different levels [3], and show a different ability to complement the growth defect in yeast S. cerevisiae devoid of the endogenous porin [4], indicating that either they have different capacities to be translocated in the OMM or they have really different pore-forming activity, at least when expressed in S. cerevisiae [4-5]. We are trying to elucidate the functional role of VDAC3, the least abundant and most elusive member of the family, with various molecular and predictive approaches. In our hands the reconstitution of recombinant human VDAC3 gave origin to an unexpected pore-formation activity, with pores by far smaller than those of other isoforms [5]. The molecular dynamics analysis of the three isoforms does not support such activity in terms of predicted diameters [6]. The definition of the VDAC3 interactome [7] shows that various cytosolic or cytoskeletal proteins can influence the activity of the protein. Other evidence will be reported to explain this puzzling behavior of the VDAC3 isoform.