title: The non-apoptotic action of Bcl-xL: regulating Ca(2+) signaling and bioenergetics at the ER-mitochondrion interface.
abstract: 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-xL was detected at the ER-mitochondrion interface or MAM (mitochondria-associated ER membrane) in association with type 3 inositol 1,4,5-trisphosphate receptors (IP3R3); an association facilitated by the BH4 and transmembrane domains of Bcl-xL. Moreover, increasing Bcl-xL 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 IP3R3-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-xL translocated to the MAM and increased its interaction with IP3R3 following extended Tg treatment. Thus, the MAM is a critical cell-signaling junction whereby Bcl-xL dynamically interacts with IP3R3 to coordinate mitochondrial Ca(2+) transfer and alters cellular metabolism in order to increase the cells' bioenergetic capacity, particularly during periods of stress.
authors.affiliation: Cellular Pathobiology Section, IRP, NIDA, NIH, DHHS, 333 Cassell Drive, Baltimore, MD, 21224, USA.|Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD, 21218, USA.|Division of Biotechnology Review and Research II, FDA/CDER/OPS/OBP, 10903 New Hampshire Ave, Silver Spring, MD, 20993, USA.
authors.forename: Abasha
authors.initials: A
authors.lastname: Williams
authors.affiliation: Cellular Pathobiology Section, IRP, NIDA, NIH, DHHS, 333 Cassell Drive, Baltimore, MD, 21224, USA.|Seiwakai Nishikawa Hospital, 293-2 Minato-Machi, Hamada, Shimane, 697-0052, Japan.
authors.forename: Teruo
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD, 21218, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Wolozny
authors.affiliation: Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD, 21218, USA.
authors.forename: Bojiao
authors.initials: B
authors.lastname: Yin
authors.affiliation: Cellular Pathobiology Section, IRP, NIDA, NIH, DHHS, 333 Cassell Drive, Baltimore, MD, 21224, USA.
authors.forename: Tzu-Chieh
authors.initials: TC
authors.lastname: Su
authors.affiliation: Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD, 21218, USA. beten@jhu.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Betenbaugh
authors.affiliation: Cellular Pathobiology Section, IRP, NIDA, NIH, DHHS, 333 Cassell Drive, Baltimore, MD, 21224, USA. tsu@intra.nida.nih.gov.
authors.forename: Tsung-Ping
authors.initials: TP
authors.lastname: Su
mesh_terms: D000818:Animals; D001692:Biological Transport; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D004734:Energy Metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism / Q000502:physiology*
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D051020:bcl-X Protein; D002118:Calcium
keywords: Bcl-xL; Bioenergetics; Calicum signaling; ER; IP3R3; MAM; Mitochondria