title: The BH4 domain of anti-apoptotic Bcl-XL, but not that of the related Bcl-2, limits the voltage-dependent anion channel 1 (VDAC1)-mediated transfer of pro-apoptotic Ca2+ signals to mitochondria.
abstract: Excessive Ca(2+) fluxes from the endoplasmic reticulum to the mitochondria result in apoptotic cell death. Bcl-2 and Bcl-XL proteins exert part of their anti-apoptotic function by directly targeting Ca(2+)-transport systems, like the endoplasmic reticulum-localized inositol 1,4,5-trisphosphate receptors (IP3Rs) and the voltage-dependent anion channel 1 (VDAC1) at the outer mitochondrial membranes. We previously demonstrated that the Bcl-2 homology 4 (BH4) domain of Bcl-2 protects against Ca(2+)-dependent apoptosis by binding and inhibiting IP3Rs, although the BH4 domain of Bcl-XL was protective independently of binding IP3Rs. Here, we report that in contrast to the BH4 domain of Bcl-2, the BH4 domain of Bcl-XL binds and inhibits VDAC1. In intact cells, delivery of the BH4-Bcl-XL peptide via electroporation limits agonist-induced mitochondrial Ca(2+) uptake and protects against staurosporine-induced apoptosis, in line with the results obtained with VDAC1(-/-) cells. Moreover, the delivery of the N-terminal domain of VDAC1 as a synthetic peptide (VDAC1-NP) abolishes the ability of BH4-Bcl-XL to suppress mitochondrial Ca(2+) uptake and to protect against apoptosis. Importantly, VDAC1-NP did not affect the ability of BH4-Bcl-2 to suppress agonist-induced Ca(2+) release in the cytosol or to prevent apoptosis, as done instead by an IP3R-derived peptide. In conclusion, our data indicate that the BH4 domain of Bcl-XL, but not that of Bcl-2, selectively targets VDAC1 and inhibits apoptosis by decreasing VDAC1-mediated Ca(2+) uptake into the mitochondria.
authors: From the Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, and giovanni.monaco@med.kuleuven.be.
authors: Giovanni
authors: G
authors: Monaco
authors: the Physiology Group, Department of Basic Medical Sciences, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium.
authors: Elke
authors: E
authors: Decrock
authors: the Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel, and.
authors: Nir
authors: N
authors: Arbel
authors: Laboratory of Cell Death Research and Therapy, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium.
authors: Alexander R
authors: AR
authors: van Vliet
authors: From the Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, and the Laboratory of Cellular Physiology, Department of Neuroscience Imaging and Clinical Sciences, Faculty of Pharmacy, "G. D'annunzio" University, 66013 Chieti, Italy.
authors: Rita M
authors: RM
authors: La Rovere
authors: From the Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, and.
authors: Humbert
authors: H
authors: De Smedt
authors: From the Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, and.
authors: Jan B
authors: JB
authors: Parys
authors: Laboratory of Cell Death Research and Therapy, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium.
authors: Patrizia
authors: P
authors: Agostinis
authors: the Physiology Group, Department of Basic Medical Sciences, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium.
authors: Luc
authors: L
authors: Leybaert
authors: the Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel, and.
authors: Varda
authors: V
authors: Shoshan-Barmatz
authors: From the Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, and geert.bultynck@med.kuleuven.be.
authors: Geert
authors: G
authors: Bultynck
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D020013:Calcium Signaling; D002478:Cells, Cultured; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D008969:Molecular Sequence Data; D050995:Voltage-Dependent Anion Channel 1 / Q000502:physiology*; D051020:bcl-X Protein / Q000502:physiology*
chemical_list: C494812:Bcl2l1 protein, mouse; D051020:bcl-X Protein; D050995:Voltage-Dependent Anion Channel 1
keywords: Anti-apoptotic Bcl-2 Family Members; B-cell Lymphoma 2 (Bcl-2) Family; Calcium Channel; Calcium Intracellular Release; Calcium Signaling; Endoplasmic Reticulum; MAM; Mitochondrial Apoptosis; Mitochondrial Cross-talk; VDAC1; Voltage-dependent Anion Channel (VDAC)