Mitochondrial Voltage-Dependent Anion Channels Implicated in Ca2+ Signaling

Rapizzi et al. have demonstrated that the voltage-dependent anion channel (VDAC) of the mitochondrial outer membrane plays an important role in transmitting Ca2+ signals from the endoplasmic reticulum (ER) to the mitochondria. Recent research indicates that mitochondria respond to localized increases in the concentration of free intracellular Ca2+ ([Ca2+]i) near release sites in the ER by increasing mitochondrial Ca2+ concentrations ([Ca2+]m), a response that may be important in limiting bulk changes in [Ca2+]i and in eliciting changes in mitochondrial function. The specific mechanisms whereby localized Ca2+ signaling between ER and mitochondria occurs, however, and the identity of the molecules involved, have remained unclear. Using aequorin derivatives and Ca2+-sensitive green fluorescent protein (GFP) derivatives specifically targeted to the mitochondria or ER, Rapizzi et al. showed that overexpression of tagged VDACs enhanced histamine-stimulated increases in [Ca2+]m in HeLa cells and carbachol-stimulated increases in [Ca2+]m in skeletal myotubes dependent on Ca2+ release from ER stores, without changing Ca2+ handling by the ER or mitochondrial Ca2+ uptake in HeLa cells permeabilized with digitonin. Experiments with targeted aequorin derivatives with different Ca2+ binding affinities, together with immunocytochemical analyses of the spatial relationship among ER, VDAC, and mitochondria, suggested that VDAC overexpression enhanced mitochondrial Ca2+ permeability at ER-mitochondrial contact sites without expanding the area of contact. HeLa cells overexpressing VDACs showed increased sensitivity to ceramide-induced alterations in mitochondrial morphology and cell death, which suggests an important functional role for VDAC-mediated increases in [Ca2+]m in apoptosis. E. Rapizzi, P. Pinton, G. Szabadkai, M. R. Wieckowski, G. Vandecasteele, G. Baird, R. A. Tuft, K. E. Fogarty, R. Rizzuto, Recombinant expression of the voltage-dependent anion channel enhances the transfer of Ca2+ microdomains to mitochondria. J. Cell Biol. 159, 613-624 (2002). [Abstract] [Full Text]