The non-apoptotic action of Bcl-x L : regulating Ca 2+ signaling and bioenergetics at the ER-mitochondrion interface

Bcl-2 family proteins are known to competitively regulate Ca 2+ ; 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 ( m itochondria- a ssociated ER m embrane) 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 Ca 2+ levels upon ER Ca 2+ depletion induced by short-term, non-apoptotic incubation with thapsigargin (Tg), while concomitantly reducing cytosolic Ca 2+ 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 Ca 2+ transfer and alters cellular metabolism in order to increase the cells’ bioenergetic capacity, particularly during periods of stress.