title: Regulation of VDAC trafficking modulates cell death.
abstract: The voltage-dependent anion channel (VDAC) and mitochondria-associated hexokinase (HxK) have crucial roles in both cell survival and death. Both the individual abundances and their ratio seem to influence the balance of survival and death and are thus critical in scenarios, such as neurodegeneration and cancer. Elevated levels of both VDAC and HxK have been reported in cancerous cells. Physical interaction is surmised and specific residues or regions involved have been identified, but details of the interaction and the mechanism by which it modulates survival are yet to be elucidated. We and others have shown that heterologous expression of VDAC can induce cell death, which can be mitigated by concomitant overexpression of HxK. We have also observed that upon overexpression, fluorescently tagged VDAC is distributed between the cytosol and mitochondria. In this study, we show that cell death ensues only when the protein, which is synthesized on cytoplasmic ribosomes, migrates to the mitochondrion. Further, coexpression of rat HxK II (rHxKII) can delay the translocation of human VDAC1 (hVDAC1) protein to mitochondria and thereby inhibit VDAC-induced cell death. Variation in the level of HxK protein as seen endogenously in different cell lines, or as experimentally manipulated by silencing and overexpression, can lead to differential VDAC translocation kinetics and related cell death. The N-terminal region of HxK and the Glu73 residue of hVDAC1, which have previously been implicated in a physical interaction, are required for cytosolic retention of VDAC. Finally, we show that, in otherwise unperturbed cells in culture, there is a small but significant amount of soluble VDAC in the cytosol present in a complex with HxK. This complex could well determine how a cell is poised with respect to incoming thanatopic signals, thereby tilting the survival/death balance in pharmacologically interesting situations, such as neurodegeneration and cancer.
authors.affiliation: Laboratory of Membrane Biophysics, National Centre for Biological Sciences, TIFR , Bangalore 560065, India.
authors.forename: Ashvini K
authors.initials: AK
authors.lastname: Dubey
authors.affiliation: Laboratory of Membrane Biophysics, National Centre for Biological Sciences, TIFR, Bangalore 560065, India; Department of Crop Physiology, GKVK, University of Agricultural Sciences, Bangalore 560065, India.
authors.forename: Ashwini
authors.initials: A
authors.lastname: Godbole
authors.affiliation: Laboratory of Membrane Biophysics, National Centre for Biological Sciences, TIFR , Bangalore 560065, India.
authors.forename: M K
authors.initials: MK
authors.lastname: Mathew