An Interaction between Bcl-x(L) and the Voltage-dependent Anion Channel (VDAC) Promotes Mitochondrial Ca2+ Uptake

作者：Huang Huiya; Hu Xiangxin; Eno Colins O; Zhao Guoping; Li Chi; White Carl^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2013, 288(27): 19870-19881.

DOI：10.1074/jbc.M112.448290

The role of the antiapoptotic protein Bcl-x(L) in regulating mitochondrial Ca2+ ([Ca2+](mito)) handling was examined in wild-type (WT) and Bcl-x(L) knock-out (Bcl-x(L)-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-x(L)-KO. In permeabilized cells, stepping external [Ca2+] from 0 to 3+ M also produced a larger [Ca2+](mito) uptake in WT; moreover, the [Ca2+](mito) uptake capacity of Bcl-x(L)-KO cells was restored by re-expression of mitochondrially targeted Bcl-x(L). Bcl-x(L) 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-x(L). Bcl-x(L) interacted with VDAC1 and -3 isoforms, and peptides based on the VDAC sequence disrupted Bcl-x(L) 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-x(L) interacts functionally with VDAC1 and -3 but not VDAC2. Thus, an interaction between Bcl-x(L) and VDAC promotes matrix Ca2+ accumulation by increasing Ca2+ transfer across the outer mitochondrial membrane.

• 出版日期2013-7-5