Calcium Handling 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]

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VIRTUAL JOURNAL
Recombinant expression of the voltage-dependent anion channel enhances the transfer of Ca²⁺ microdomains to mitochondria

Elena Rapizzi, Paolo Pinton, György Szabadkai, Mariusz R. Wieckowski, Grégoire Vandecasteele, Geoff Baird, Richard A. Tuft, Kevin E. Fogarty, and Rosario Rizzuto (25 November 2002)
J. Cell Biol. 159 (4), 613. [DOI: 10.1083/jcb.200205091]
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