The Mitochondrial Voltage-Dependent Anion Channel 1, Ca2+ Transport, Apoptosis, and Their Regulation

Varda Shoshan-Barmatz,Alon Meir,Soumasree De

doi:10.3389/fonc.2017.00060

Abstract

In the outer mitochondrial membrane, the voltage-dependent anion channel 1 (VDAC1) functions in cellular Ca2+ homeostasis by mediating the transport of Ca2+ in and out of mitochondria. VDAC1 is highly Ca2+-permeable and modulates Ca2+ access to the mitochondrial intermembrane space. Intramitochondrial Ca2+ controls energy metabolism by enhancing the rate of NADH production via modulating critical enzymes in the tricarboxylic acid cycle and fatty acid oxidation. Mitochondrial [Ca2+] is regarded as an important determinant of cell sensitivity to apoptotic stimuli and was proposed to act as a “priming signal,” sensitizing the organelle and promoting the release of pro-apoptotic proteins. However, the precise mechanism by which intracellular Ca2+ ([Ca2+]i) mediates apoptosis is not known. Here, we review the roles of VDAC1 in mitochondrial Ca2+ homeostasis and in apoptosis. Accumulated evidence shows that apoptosis-inducing agents act by increasing [Ca2+]i and that this, in turn, augments VDAC1 expression levels. Thus, a new concept of how increased [Ca2+]i activates apoptosis is postulated. Specifically, increased [Ca2+]i enhances VDAC1 expression levels, followed by VDAC1 oligomerization, cytochrome c release, and subsequently apoptosis. Evidence supporting this new model suggesting that upregulation of VDAC1 expression constitutes a major mechanism by which apoptotic stimuli induce apoptosis with VDAC1 oligomerization being a molecular focal point in apoptosis regulation is presented. A new proposed mechanism of pro-apoptotic drug action, namely Ca2+-dependent enhancement of VDAC1 expression, provides a platform for developing a new class of anticancer drugs modulating VDAC1 levels via the promoter and for overcoming the resistance of cancer cells to chemotherapy.

Highlights

We review the roles of voltage-dependent anion channel 1 (VDAC1) in mitochondrial Ca2+ homeostasis and in apoptosis
Accumulated evidence shows that apoptosis-inducing agents act by increasing [Ca2+]i and that this, in turn, augments VDAC1 expression levels
Increased [Ca2+]i enhances VDAC1 expression levels, followed by VDAC1 oligomerization, cytochrome c release, and subsequently apoptosis. Evidence supporting this new model suggesting that upregulation of VDAC1 expression constitutes a major mechanism by which apoptotic stimuli induce apoptosis with VDAC1 oligomerization being a molecular focal point in apoptosis regulation is presented

Summary

Efflux and Its Regulation

Mitochondrial Ca2+ is mainly determined by the balance between influx through the MCU and efflux via NCLX [90]. It was demonstrated that a panel of apoptotic inducers, such as UV irradiation, H2O2, etoposide, cisplatin, or selenite, elevated [Ca2+]i and upregulated VDAC1 expression levels in a Ca2+-dependent manner (Table 1), resulting in VDAC1 oligomerization, Cyto c release, and subsequent apoptosis [140, 141] (Figure 2). It has been shown that the sensitivity of the CD45-positive (CD45+) U266 myeloma cell line to various apoptotic stimuli is well correlated with the elevated levels of VDAC1 expression that follow Ca2+ signals in response to apoptosis stimulation [169, 175] This suggests that apoptosis-inducing agents act by increasing [Ca2+]i and that this, in turn, leads to an upregulation of VDAC1 expression, which is connected to apoptosis induction (Table 1). Suggest that the upregulation of VDAC1 expression constitutes a major mechanism by which apoptosis inducers lead to apoptosis (Figure 2)

Cancer cell type

Hepatoma cells