An oligonucleotide-based microarray analysis of 9,500 genes and expressed sequence tags (ESTs) demonstrated that the type 1 inositol 1,4,5-trisphosphate receptor (IP₃R) was significantly down-regulated in Bcl-X_L-expressing as compared with control cells. This result was confirmed at the mRNA and protein levels by Northern and Western blot analyses of two independent hematopoietic cell lines and murine primary T cells. Bcl-X_L expression resulted in a dose-dependent decrease in IP₃R protein. IP₃R expression is regulated as part of a mitochondrion-to-nucleus stress-responsive pathway. The uncoupling of mitochondrial oxidative phosphorylation resulted in induction of binding of the transcription factor NFATc2 to the IP₃R promoter and transcriptional activation of IP₃R. Expression of Bcl-X_L led to a decreased induction of both NFATc2 DNA binding to the IP₃R promoter and IP₃R expression in response to the inhibition of mitochondrial oxidative phosphorylation. The Bcl-X_L-dependent decrease in IP₃R expression also correlated with a reduced T cell antigen receptor ligation-induced Ca²⁺ flux in Bcl-X_L transgenic murine T cells, and microsomal vesicles prepared from Bcl-X_L-overexpressing cells exhibited lower IP₃-mediated Ca²⁺ release capacity. Furthermore, reintroducing IP₃R into Bcl-X_L-transfected cells partially reversed Bcl-X_L-dependent anti-apoptotic activity. These results suggest that even under non-apoptotic conditions, expression of Bcl-2-family proteins influences a signaling network that links changes in mitochondrial metabolism to alterations in nuclear gene expression.