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

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Abstract

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-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 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 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 Ca2+ transfer and alters cellular metabolism in order to increase the cells’ bioenergetic capacity, particularly during periods of stress.

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Abbreviations

AUC:

Area under the curve

BAPTA:

1,2-bis(o-aminophenoxy)ethane-N,N,N’,N’-tetraacetic acid

Bcl-2:

B-cell lymphoma-2

Bcl-xL :

B-cell lymphoma-extra large

BiP:

Binding immunoglobulin protein

Cyto:

Cytosol

DsRed:

Discosoma sp.red fluorescent protein

ERp75:

Endoplasmic reticulum resident protein 75

FRET:

Fluorescence energy resonance transfer

Grp75:

Glucose regulated protein 75

HcRed:

Heteractis crispa far-red fluorescent protein

HEPES:

4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

His:

Histidine

IP3R:

Inositol 1,4,5-trisphophate receptor

IRE1:

Inositol-requiring enzyme 1

KHB:

Krebs-HEPES Buffer

MAM:

Mitochondria-associated ER membrane

Mfn2:

Mitofusin 2

Mito:

Mitochondria

NAD:

Nicotinamide adenine dinucleotide

NADH:

Nicotinamide adenine dinucleotide reduced

NP62:

Nucleoporin 62

OMM:

Outer mitochondria membrane

PERK:

RNA-dependent protein kinase-like ER kinase

P1:

Whole cell/nuclear

P3:

Microsome

RFU:

Relative fluorescence units

RLU:

Relative fluorescence units

Sig-1R:

σ-1 receptor

TCA:

Tricarboxylic acid

Tg:

Thapsigargin

TM:

Transmembrane

Tomm20:

Translocase of the outer mitochondrial membrane

Tun:

Tunicamycin

VDAC:

Voltage-gated anion channel

YFP:

Yellow fluorescent protein.

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Acknowledgments

The authors would like to thank R.Y. Tsien (University of California, San Diego, CA) for generously providing D1ER Ca2+ cameleon. We additionally thank J.M. Hardwick (Johns Hopkins University, Baltimore, MD) for providing Bcl-xL ΔBH4 and Bcl-xL ΔTM constructs, and Biolog, Inc. for providing the use of its Omnilog microarray system. This work is supported by the NSF and the Intramural Research Program, National Institute of Drug Abuse, NIH, DHHS.

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Author notes

  1. Abasha Williams

    Present address: Division of Biotechnology Review and Research II, FDA/CDER/OPS/OBP, 10903 New Hampshire Ave, Silver Spring, MD, 20993, USA

  2. Teruo Hayashi

    Present address: Seiwakai Nishikawa Hospital, 293-2 Minato-Machi, Hamada, Shimane, 697-0052, Japan

Authors and Affiliations

  1. Cellular Pathobiology Section, IRP, NIDA, NIH, DHHS, 333 Cassell Drive, Baltimore, MD, 21224, USA

    Abasha Williams, Teruo Hayashi, Tzu-Chieh Su & Tsung-Ping Su

  2. Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD, 21218, USA

    Abasha Williams, Daniel Wolozny, Bojiao Yin & Michael J. Betenbaugh

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Williams, A., Hayashi, T., Wolozny, D. et al. The non-apoptotic action of Bcl-xL: regulating Ca2+ signaling and bioenergetics at the ER-mitochondrion interface. J Bioenerg Biomembr 48, 211–225 (2016). https://doi.org/10.1007/s10863-016-9664-x

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