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Bcl-2 family in inter-organelle modulation of calcium signaling; roles in bioenergetics and cell survival

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Abstract

Bcl-2 family proteins, known for their apoptosis functioning at the mitochondria, have been shown to localize to other cellular compartments to mediate calcium (Ca2+) signals. Since the proper supply of Ca2+ in cells serves as an important mechanism for cellular survival and bioenergetics, we propose an integrating role for Bcl-2 family proteins in modulating Ca2+ signaling. The endoplasmic reticulum (ER) is the main Ca2+ storage for the cell and Bcl-2 family proteins competitively regulate its Ca2+ concentration. Bcl-2 family proteins also regulate the flux of Ca2+ from the ER by physically interacting with inositol 1,4,5-trisphosphate receptors (IP3Rs) to mediate their opening. Type 1 IP3Rs reside at the bulk ER to coordinate cytosolic Ca2+ signals, while type 3 IP3Rs reside at mitochondria-associated ER membrane (MAM) to facilitate mitochondrial Ca2+ uptake. In healthy cells, mitochondrial Ca2+ drives pyruvate into the citric acid (TCA) cycle to facilitate ATP production, while a continuous accumulation of Ca2+ can trigger the release of cytochrome c, thus initiating apoptosis. Since multiple organelles and Bcl-2 family proteins are involved in Ca2+ signaling, we aim to clarify the role that Bcl-2 family proteins play in facilitating Ca2+ signaling and how mitochondrial Ca2+ is relevant in both bioenergetics and apoptosis. We also explore how these insights could be useful in controlling bioenergetics in apoptosis-resistant cell lines.

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

    Abasha Lewis & Michael J. Betenbaugh

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

    Abasha Lewis & Tsung-Ping Su

  3. Seiwakai Nishikawa Hospital, 293-2 Minato-Machi, Hamada, Shimane, Japan

    Teruo Hayashi

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  1. Abasha Lewis
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Lewis, A., Hayashi, T., Su, TP. et al. Bcl-2 family in inter-organelle modulation of calcium signaling; roles in bioenergetics and cell survival. J Bioenerg Biomembr 46, 1–15 (2014). https://doi.org/10.1007/s10863-013-9527-7

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