Voltage-dependent anion channels: different isoforms for different functions

The Voltage-dependent anion channel (VDAC) is the most abundant protein of the outer mitochondrial membrane (OMM) and mediates the flow of ions and metabolites between the cytoplasm and the mitochondrial network. Here we reveal novel and unexpected roles of this protein in the regulation of Ca2+ signaling, cell death and autophagy, throwing light on the differential contribution of the three mammalian isoforms in these cellular processes. In particular, we show that: i) VDAC is physically linked to the endoplasmic reticulum Ca2+ release channel inositol-1,4,5-trisphosphate receptor (IP3R), through the molecular chaperone grp75 and the functional coupling of these channel directly enhances Ca2+ accumulation in mitochondria; ii) the different VDAC isoforms share common Ca2+ channelling properties in living cells but VDAC1 is the only isotype selectively coupled to the ER Ca2+ releasing machinery, thus laying the foundations for a preferential route specifically transmitting Ca2+-mediated cell death signals between the two organelles; iii) VDAC2 is selectively required for the induction of the autophagic process through the establishment of specific protein-protein interactions and the consequent assembly of macromolecular complexes at the OMM level involved in nutrient sensing mediated by the mammalian Target Of Rapamycin (mTOR) signaling pathway. These data highlight the pleiotropic functions of VDAC and its role as central regulator of cell patho-physiology.