Modulation of Ca2+ Signaling by Anti-apoptotic B-Cell Lymphoma 2 Proteins at the Endoplasmic Reticulum-Mitochondrial Interface

Abstract

Mitochondria are important regulators of cell death and cell survival. Mitochondrial Ca²⁺ levels are critically involved in both of these processes. On the one hand, excessive mitochondrial Ca²⁺ leads to Ca²⁺-induced mitochondrial outer membrane permeabilization and thus apoptosis. On the other hand, mitochondria need Ca²⁺ in order to efficiently fuel the tricarboxylic acid cycle and maintain adequate mitochondrial bioenergetics. For obtaining this Ca²⁺, the mitochondria are largely dependent on close contact sites with the endoplasmic reticulum (ER), the so-called mitochondria-associated ER membranes. There, the inositol 1,4,5-trisphosphate receptors are responsible for the Ca²⁺ release from the ER. It comes as no surprise that this Ca²⁺ release from the ER and the subsequent Ca²⁺ uptake at the mitochondria are finely regulated. Cancer cells often modulate ER-Ca²⁺ transfer to the mitochondria in order to promote cell survival and to inhibit cell death. Important regulators of these Ca²⁺ signals and the onset of cancer are the B-cell lymphoma 2 (Bcl-2) family of proteins. An increasing number of reports highlight the ability of these Bcl-2-protein family members to finely regulate Ca²⁺ transfer from ER to mitochondria both in healthy cells and in cancer. In this review, we focus on recent insights into the dynamic regulation of ER-mitochondrial Ca²⁺ fluxes by Bcl-2-family members and how this impacts cell survival, cell death and mitochondrial energy production.

Keywords: Bcl-2; Ca2+-transport systems; IP3 receptors; apoptosis; autophagy; endoplasmic reticulum–mitochondria contact sites; mitochondrial bio energetics; voltage-dependent anion channels.

Figure 1

B-cell lymphoma (Bcl)-2 and Bcl-X_L and their targets in Ca²⁺ signaling, inositol 1,4,5-trisphosphate receptor (IP₃R) and voltage-dependent anion channel 1 (VDAC1), are present in the mitochondria-associated endoplasmic reticulum membranes (MAMs). Representative immunoblots showing the presence of VDAC1, IP₃Rs, Bcl-2, and Bcl-X_L in the MAMs of MEFs. Calnexin (CNX) and cytochrome c (Cyt c) served as specific MAMs and mitochondrial markers, respectively. These data were originally published in Journal of Biological Chemistry with following reference: Monaco et al. (45). © The American Society for Biochemistry and Molecular Biology. Authors of articles in Journal of Biological Chemistry have the rights to reuse their own material and are automatically granted a permission to reuse figures from their articles in future works. The original results have been produced by Dr. Alex van Vliet in the laboratory of Prof. Patrizia Agostinis (KU Leuven, Belgium).

Figure 2

Modulation of endoplasmic reticulum (ER) to mitochondrial Ca²⁺ transfers by anti-apoptotic B-cell lymphoma (Bcl)-2 proteins. ER to mitochondrial Ca²⁺ transfers are critical for the regulation of cell death and cell survival decisions. In order to fuel the tricarboxylic acid (TCA) cycle, a continuous influx of Ca²⁺ into the mitochondria is required (green arrow), thereby promoting cell survival. Excessive mitochondrial Ca²⁺ uptake leads to Ca²⁺-induced mitochondrial outer membrane permeabilization (MOMP) and cell death (red arrow). The anti-apoptotic side of the Bcl-2-protein family regulates these Ca²⁺ transfers at both organelles. During pro-survival Ca²⁺ signaling at the ER, Bcl-2, Bcl-X_L, and Mcl-1 modulate inositol 1,4,5-trisphosphate receptor (IP₃R)-mediated Ca²⁺ release to generate Ca²⁺ oscillations. At the mitochondria, Bcl-X_L and Mcl-1 can increase voltage-dependent anion channel 1 (VDAC1)-mediated Ca²⁺ uptake. Combining the effects at the two organelles results in an efficient and finely regulated Ca²⁺ uptake at the mitochondria, which increases mitochondrial bioenergetics and promotes cell survival. In addition, Mcl-1 and Bcl-X_L target the F₀F₁ ATP synthase, thereby regulating ATP-production. During pro-death signaling, Bcl-2 and Bcl-X_L can inhibit both pro-apoptotic Ca²⁺ release from the IP₃R and the Ca²⁺ uptake into the mitochondria via VDAC. Finally, abolishing ER to mitochondrial Ca²⁺ transfers by either blocking IP₃Rs or knocking down the mitochondrial Ca²⁺ uniporter (MCU) induces autophagy. When this is coupled to decreased cell proliferation (healthy cells), this increase in autophagy may rescue the cell. However, when proliferation is not halted (cancer cells) this results in cell death.