The non-apoptotic action of Bcl-xL: regulating Ca2+ signaling and bioenergetics at the ER-mitochondrion interface

Bcl-2 family proteins are known to competitively regulate Ca2+; however, the specific inter-organelle signaling pathways and related cellular functions are not fully elucidated. In this study, a portion of Bcl-x(L) was detected at the ER-mitochondrion interface or MAM (mitochondria-associated ER membrane) in association with type 3 inositol 1,4,5-trisphosphate receptors (IP(3)R3); an association facilitated by the BH4 and transmembrane domains of Bcl-x(L). Moreover, increasing Bcl-x(L) expression enhanced transient mitochondrial Ca2+ levels upon ER Ca2+ depletion induced by short-term, non-apoptotic incubation with thapsigargin (Tg), while concomitantly reducing cytosolic Ca2+ release. These mitochondrial changes appear to be IP(3)R3-dependent and resulted in decreased NAD/NADH ratios and higher electron transport chain oxidase activity. Interestingly, extended Tg exposure stimulated ER stress, but not apoptosis, and further enhanced TCA cycling. Indeed, confocal analysis indicated that Bcl-x(L) translocated to the MAM and increased its interaction with IP(3)R3 following extended Tg treatment. Thus, the MAM is a critical cell-signaling junction whereby Bcl-x(L) dynamically interacts with IP(3)R3 to coordinate mitochondrial Ca2+ transfer and alters cellular metabolism in order to increase the cells' bioenergetic capacity, particularly during periods of stress.