The Mitochondrial Voltage-Dependent Anion Channel 1, Ca(2+) Transport, Apoptosis, and Their Regulation.

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The Mitochondrial Voltage-Dependent Anion Channel 1, Ca(2+) Transport, Apoptosis, and Their Regulation.

Front Oncol. 2017;7:60

Authors: Shoshan-Barmatz V, De S, Meir A

Abstract
In the outer mitochondrial membrane, the voltage-dependent anion channel 1 (VDAC1) functions in cellular Ca(2+) homeostasis by mediating the transport of Ca(2+) in and out of mitochondria. VDAC1 is highly Ca(2+)-permeable and modulates Ca(2+) access to the mitochondrial intermembrane space. Intramitochondrial Ca(2+) controls energy metabolism by enhancing the rate of NADH production via modulating critical enzymes in the tricarboxylic acid cycle and fatty acid oxidation. Mitochondrial [Ca(2+)] 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 Ca(2+) ([Ca(2+)]i) mediates apoptosis is not known. Here, we review the roles of VDAC1 in mitochondrial Ca(2+) homeostasis and in apoptosis. Accumulated evidence shows that apoptosis-inducing agents act by increasing [Ca(2+)]i and that this, in turn, augments VDAC1 expression levels. Thus, a new concept of how increased [Ca(2+)]i activates apoptosis is postulated. Specifically, increased [Ca(2+)]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 Ca(2+)-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.

PMID: 28443244 [PubMed - in process]

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