VDAC1 at the crossroads of cell metabolism, apoptosis and cell stress

Authors:

Varda Shoshan-Barmatz1, Eduardo N. Maldonado2 and Yakov Krelin1
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Affiliations:

1 Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel.

2 Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC, USA.

Keywords: 

apoptosis, cancer, metabolism, mitochondria, VDAC1.

Abbreviations:

Aβ – Amyloid beta,

AD – Alzheimer’s disease,

ALS – amyotrophic lateral sclerosis,

AIF - apoptosis-inducing factor,

ANT - adenine nucleotide translocase,

Bcl-2 - B-cell lymphoma 2,

CSC – cancer stem cell,

CVD – cardiovascular disease,

Cyto c - cytochrome c,

DIDS - 4,4-diisothiocyanostilbene-2,2-disulfonic acid,

HK – hexokinase,

IMM - inner mitochondrial membrane,

IMS – intermembrane space,

NSCLC - non-small cell lung cancer,

miRNA – micro RNA

OMM - outer mitochondrial membrane,

OXPHOS – oxidative phosphorylation,

PTP - permeability transition pore,

RNAi - RNA interference,

ROS - reactive oxygen species,

TSPO - translocator protein,

T2D – type 2 diabetes,

VDAC - voltage-dependent anion channel.

Corresponding Author(s):

Prof. Varda Shoshan-Barmatz, Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; Fax : 972-8-647 2992 vardasb@bgu.ac.il

Conflict of interest statement:

The authors declare no conflict of interest.

Please cite this article as:

Varda Shoshan-Barmatz, Eduardo N. Maldonado and Yakov Krelin (2017). VDAC1 at the crossroads of cell metabolism, apoptosis and cell stress. Cell Stress 1(1): 11-36. doi: 10.15698/cst2017.10.104

© 2017 Shoshan-Barmatz et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.

Abstract:

This review presents current knowledge related to VDAC1 as a multi-functional mitochondrial protein acting on both sides of the coin, regulating cell life and death, and highlighting these functions in relation to disease. It is now recognized that VDAC1 plays a crucial role in regulating the metabolic and energetic functions of mitochondria. The location of VDAC1 at the outer mitochondrial membrane (OMM) allows the control of metabolic cross-talk between mitochondria and the rest of the cell and also enables interaction of VDAC1 with proteins involved in metabolic and survival pathways. Along with regulating cellular energy production and metabolism, VDAC1 is also involved in the process of mitochondria-mediated apoptosis by mediating the release of apoptotic proteins and interacting with anti-apoptotic proteins. VDAC1 functions in the release of apoptotic proteins located in the mitochondrial intermembrane space via oligomerization to form a large channel that allows passage of cytochrome c and AIF and their release to the cytosol, subsequently resulting in apoptotic cell death. VDAC1 also regulates apoptosis via interactions with apoptosis regulatory proteins, such as hexokinase, Bcl2 and Bcl-xL, some of which are also highly expressed in many cancers. This review also provides insight into VDAC1 function in Ca2+ homeostasis, oxidative stress, and presents VDAC1 as a hub protein interacting with over 100 proteins. Such interactions enable VDAC1 to mediate and regulate the integration of mitochondrial functions with cellular activities. VDAC1 can thus be considered as standing at the crossroads between mitochondrial metabolite transport and apoptosis and hence represents an emerging cancer drug target.