Journal of Bioenergetics and Biomembranes

, Volume 48, Issue 3, pp 211–225 | Cite as

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

  • Abasha Williams
  • Teruo Hayashi
  • Daniel Wolozny
  • Bojiao Yin
  • Tzu-Chieh Su
  • Michael J. Betenbaugh
  • Tsung-Ping Su


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.


Bcl-xL Bioenergetics Calicum signaling Mitochondria ER MAM IP3R3 



Area under the curve


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


B-cell lymphoma-2


B-cell lymphoma-extra large


Binding immunoglobulin protein




Discosoma fluorescent protein


Endoplasmic reticulum resident protein 75


Fluorescence energy resonance transfer


Glucose regulated protein 75


Heteractis crispa far-red fluorescent protein


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




Inositol 1,4,5-trisphophate receptor


Inositol-requiring enzyme 1


Krebs-HEPES Buffer


Mitochondria-associated ER membrane


Mitofusin 2




Nicotinamide adenine dinucleotide


Nicotinamide adenine dinucleotide reduced


Nucleoporin 62


Outer mitochondria membrane


RNA-dependent protein kinase-like ER kinase


Whole cell/nuclear




Relative fluorescence units


Relative fluorescence units


σ-1 receptor


Tricarboxylic acid






Translocase of the outer mitochondrial membrane




Voltage-gated anion channel


Yellow fluorescent protein.

Supplementary material

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Figure S1(PDF 211 kb)
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Figure S2(PDF 92 kb)
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Figure S6(PDF 591 kb)
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Figure S7(PDF 770 kb)
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Figure S8(PDF 104 kb)


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Copyright information

© Springer Science+Business Media New York (outside the USA) 2016

Authors and Affiliations

  • Abasha Williams
    • 1
    • 2
    • 3
  • Teruo Hayashi
    • 1
    • 4
  • Daniel Wolozny
    • 2
  • Bojiao Yin
    • 2
  • Tzu-Chieh Su
    • 1
  • Michael J. Betenbaugh
    • 2
  • Tsung-Ping Su
    • 1
  1. 1.Cellular Pathobiology Section, IRP, NIDA, NIH, DHHSBaltimoreUSA
  2. 2.Department of Chemical and Biomolecular EngineeringJohns Hopkins UniversityBaltimoreUSA
  3. 3.Division of Biotechnology Review and Research II, FDA/CDER/OPS/OBPSilver SpringUSA
  4. 4.Seiwakai Nishikawa HospitalHamadaJapan

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