An interaction between Bcl-XL and VDAC facilitates mitochondrial Ca2+ uptake and bioenergetics

The role of the anti‐apoptotic protein Bcl‐X L in regulating mitochondrial Ca 2+ ([Ca 2+ ] mito ) handling was examined in wild‐type (WT) and Bcl‐X L knockout (KO) cells. Upon application of InsP 3 ‐ generating agonists to evoke cytosolic Ca 2+ ([Ca 2+ ] cyto ) transients, [Ca 2+ ] mito uptake was larger in WT cells compared to KO. This was correlated with higher steady‐state ATP levels in intact WT cells compared to KO cells, and chelation of cytosolic Ca 2+ or uniporter knockdown reduced [ATP] to the same level in both cells. In permeabilized cells, stepping external [Ca 2+ ] from 0 to 3 μM also produced a larger [Ca 2+ ] mito uptake in the WT, and the [Ca 2+ ] mito uptake capacity of KO cells was restored only by re‐expression of mitochondrially but not ER‐targeted Bcl‐X L . Bcl‐X L enhancement of [Ca 2+ ] 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 Ca 2+ permeability that directly interacts with Bcl‐X L . Application of peptides based on the VDAC1 sequence disrupted Bcl‐X L ‐VDAC interactions and reduced [Ca 2+ ] mito uptake and ATP levels in the WT but not in KO cells. Taken together, these data suggest that Bcl‐X L facilitates mitochondrial Ca 2+ loading and bioenergetics by regulating VDAC Ca 2+ permeability.