The role of calcium in VDAC1 oligomerization and mitochondria-mediated apoptosis

The voltage-dependent anion channel (VDAC), located at the outer mitochondria membrane (OMM), mediates interactions between mitochondria and other parts of the cell by transporting anions, cations, ATP, Ca2+, and metabolites. Substantial evidence points to VDAC1 as being a key player in apoptosis, regulating the release of apoptogenic proteins from mitochondria, such as cytochrome c, and interacting with anti-apoptotic proteins. Recently, we demonstrated that VDAC1 oligomerization is a general mechanism common to numerous apoptogens acting via different initiating cascades and proposed that a protein-conducting channel formed within a VDAC1 homo/hetero oligomer mediates cytochrome c release. However, the molecular mechanism responsible for VDAC1 oligomerization remains unclear. Several studies have shown that mitochondrial Ca2+ is involved in apoptosis induction and that VDAC1 possesses Ca2+-binding sites and mediates Ca2+ transport across the OMM. Here, the relationship between the cellular Ca2+ level, [Ca2+](i), VDAC1 oligomerization and apoptosis was studied. Decreasing [Ca2+](i) using the cell-permeable Ca2+ chelating reagent BAPTA-AM was found to inhibit VDAC1 oligomerization and apoptosis, while increasing [Ca2+]i using Ca2+ ionophore resulted in VDAC1 oligomerization and apoptosis induction in the absence of apoptotic stimuli. Moreover, induction of apoptosis elevated [Ca2+](i), concomitantly with VDAC1 oligomerization. AzRu-mediated inhibition of mitochondrial Ca2+ transport decreased VDAC1 oligomerization, suggesting that mitochondrial Ca2+ is required for VDAC1 oligomerization. In addition, increased [Ca2+](i) levels up-regulate VDAC1 expression. These results suggest that Ca2+ promotes VDAC1 oligomerization via activation of a yet unknown signaling pathway or by increasing VDAC1 expression, leading to apoptosis. This article is part of a Special Issue entitled: 12th European Symposium on Calcium. (C) 2013 Published by Elsevier B.V.