Mitochondrial VDAC1: A Key Gatekeeper as Potential Therapeutic Target - PubMed (original) (raw)

Review

Mitochondrial VDAC1: A Key Gatekeeper as Potential Therapeutic Target

Amadou K S Camara et al. Front Physiol. 2017.

Abstract

Mitochondria are the key source of ATP that fuels cellular functions, and they are also central in cellular signaling, cell division and apoptosis. Dysfunction of mitochondria has been implicated in a wide range of diseases, including neurodegenerative and cardiac diseases, and various types of cancer. One of the key proteins that regulate mitochondrial function is the voltage-dependent anion channel 1 (VDAC1), the most abundant protein on the outer membrane of mitochondria. VDAC1 is the gatekeeper for the passages of metabolites, nucleotides, and ions; it plays a crucial role in regulating apoptosis due to its interaction with apoptotic and anti-apoptotic proteins, namely members of the Bcl-2 family of proteins and hexokinase. Therefore, regulation of VDAC1 is crucial not only for metabolic functions of mitochondria, but also for cell survival. In fact, multiple lines of evidence have confirmed the involvement of VDAC1 in several diseases. Consequently, modulation or dysregulation of VDAC1 function can potentially attenuate or exacerbate pathophysiological conditions. Understanding the role of VDAC1 in health and disease could lead to selective protection of cells in different tissues and diverse diseases. The purpose of this review is to discuss the role of VDAC1 in the pathogenesis of diseases and as a potentially effective target for therapeutic management of various pathologies.

Keywords: Alzheimer's disease; cardiac ischemia/reperfusion; hexokinase; mitochondria; molecular dynamics; neoplastic diseases; post-translational modification; voltage dependent anion channel.

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Figures

Figure 1

Figure 1

VDAC1 is expressed on the outer mitochondrial membrane (OMM). Together with ANT1 on the inner mitochondrial membrane (IMM) and mitochondrial creatine kinase (mCK), the VDAC1-ANT1-mCK complex regulates the exchange of ATP and ADP between the mitochondria and cytosol. VDAC1 functions as a receptor for anti- and pro-apoptotic proteins and, consequently, contributes to cell survival and cell death. *Bax/Bak binding to VDAC1 has not been definitively shown as various studies report on conflicting results; on the other hand, Bax/Bak binding to VDAC2 has been supported by more consistent results. VDAC1 oligomerization can result in increased permeability of the OMM; however, the mechanism that leads to apoptosis has not been clearly defined. Various types of post-translational modificantions (PTMs) of VDAC1 have been reported, although their impact on channel function and subsequently on mitochondrial function is not well understood.

Figure 2

Figure 2

Structure of human VDAC1 in membrane. (A) Sideview and (B) cytoplasmic topview of the beta-barrel, with basic residues in blue sticks, acidic E73 in red sticks, and ATP in spheres. (C) Significant ATP-interacting residues along permeation pathway (data adopted from Choudhary et al., 2014). (D) Currently confirmed phosphorylation sites in human VDAC1 (data adopted from Martel et al., 2014), positions of phospho-serines and phospho-threonine highlighted in red spheres. C-terminal part of the beta-barrel is omitted in (C,D) for clarity.

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