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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
Authors: Monaco, Giovanni *
Decrock, Elke *
Arbel, Nir
van Vliet, Alex
La Rovere, Rita
De Smedt, Humbert
Parys, Jan
Agostinis, Patrizia
Leybaert, Luc
Shoshan-Barmatz, Varda
Bultynck, Geert # ×
Issue Date: 3-Apr-2015
Publisher: American Society for Biochemistry and Molecular Biology
Series Title: Journal of Biological Chemistry vol:290 issue:14 pages:9150-9161
Article number: jbc.M114.622514
Abstract: Excessive Ca2+ fluxes from the endoplasmic reticulum (ER) to the mitochondria result in apoptotic cell death. Bcl-2 and Bcl-XL proteins exert part of their anti-apoptotic function by directly targeting Ca2+-transport systems, like the ER-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 BH4 domain of Bcl-2 protects against Ca2+-dependent apoptosis by binding and inhibiting IP3Rs, while 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 Ca2+ 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 Ca2+ uptake and to protect against apoptosis. Importantly, VDAC1-NP did not affect the ability of BH4-Bcl-2 to suppress agonist-induced Ca2+ 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 Ca2+ uptake into the mitochondria.
URI: 
ISSN: 0021-9258
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Molecular and Cellular Signaling
Laboratory of Cell Death Research & Therapy
* (joint) first author
× corresponding author
# (joint) last author

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