An Interaction between Bcl-xL and the Voltage-dependent Anion Channel (VDAC) Promotes Mitochondrial Ca2+ Uptake |
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Authors: | Huiya Huang Xiangxin Hu Colins O Eno Guoping Zhao Chi Li Carl White |
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Institution: | From the ‡Department of Physiology and Biophysics, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064 and ;§Molecular Targets Program, James Graham Brown Cancer Center and ;¶Departments of Medicine, Pharmacology, and Toxicology, University of Louisville, Louisville, Kentucky 40202 |
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Abstract: | The role of the antiapoptotic protein Bcl-xL in regulating mitochondrial Ca2+ (Ca2+]mito) handling was examined in wild-type (WT) and Bcl-xL knock-out (Bcl-xL-KO) mouse embryonic fibroblast cells. Inositol 1,4,5-trisphosphate-generating agonist evoked cytosolic Ca2+ transients that produced a larger Ca2+]mito uptake in WT cells compared with Bcl-xL-KO. In permeabilized cells, stepping external Ca2+] from 0 to 3 μm also produced a larger Ca2+]mito uptake in WT; moreover, the Ca2+]mito uptake capacity of Bcl-xL-KO cells was restored by re-expression of mitochondrially targeted Bcl-xL. Bcl-xL enhancement of Ca2+]mito uptake persisted after dissipation of the mitochondrial membrane potential but was absent in mitoplasts lacking an outer mitochondrial membrane. The outer membrane-localized voltage-dependent anion channel (VDAC) is a known Ca2+ permeability pathway that directly interacts with Bcl-xL. Bcl-xL interacted with VDAC1 and -3 isoforms, and peptides based on the VDAC sequence disrupted Bcl-xL binding. Peptides reduced Ca2+]mito uptake in WT but were without effect in Bcl-xL-KO cells. In addition, peptides reduced Ca2+]mito uptake in VDAC1 and VDAC3 knock-out but not VDAC1 and -3 double knock-out mouse embryonic fibroblast cells, confirming that Bcl-xL interacts functionally with VDAC1 and -3 but not VDAC2. Thus, an interaction between Bcl-xL and VDAC promotes matrix Ca2+ accumulation by increasing Ca2+ transfer across the outer mitochondrial membrane. |
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Keywords: | Bcl-2 Proteins Calcium Signaling Imaging Mitochondria Protein-Protein Interactions Voltage-dependent Anion Channel |
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