Mitochondrial VDAC1: A Key Gatekeeper as Potential Therapeutic Target

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.

A lower affinity to cytosolic proteins reveals VDAC3 isoform-specific role in mitochondrial biology

“…VDAC is the primary transport channel in the MOM, controlling mitochondria permeability and function. The vast majority of studies involving VDAC in a wide variety of mitochondria-associated pathologies focuses exclusively on VDAC1 or VDAC2, while VDAC3 channels remain poorly characterized (Shoshan-Barmatz and Ben-Hail, 2012; Reina et al, 2016b; Camara et al, 2017; Maurya and Mahalakshmi, 2017; Shoshan-Barmatz et al, 2017). The main reason for this discrepancy stems from the difficulty in obtaining stable and homogeneous VDAC3 samples for insertions in PLM, and thus the lack of quantitative in vitro characterization.…”

“…Permeability of mitochondrial membranes is crucial for normal metabolite exchange between mitochondria and the surrounding cytoplasm, where errors in this process result in a number of organelle pathologies (Camara et al, 2017). The voltage-dependent anion channel (VDAC), the major channel of the mitochondrial outer membrane (MOM), facilitates and controls the exchange of small ions and water-soluble respiratory substrates between these compartments (Colombini, 2004; Lemasters and Holmuhamedov, 2006; Rostovtseva and Bezrukov, 2008).…”

Sequence diversity of tubulin isotypes in regulation of the mitochondrial voltage-dependent anion channel

“…As the major transport channel and most abundant protein in the mitochondrial outer membrane (MOM), VDAC is responsible for most of the metabolite flux in and out of mitochondria. VDAC was shown to be involved in a wide variety of mitochondriaassociated pathologies, from various forms of cancer to neurodegeneration (17)(18)(19).…”

A size‐modified poisson–boltzmann ion channel model in a solvent of multiple ionic species: Application to voltage‐dependent anion channel

“…Attenuation of VDAC conductance due to alterations in VDAC structure under pathophysiological conditions can lead to reduction in substrate supply and ADP/ATP exchange across the inner mitochondrial membrane during oxidative phosphorylation and ATP synthesis, leading to mitochondrial dysfunction and cellular injury/death. Thus, as a major regulatory gateway for ions and metabolites (organic anions) to go into and out of mitochondria, VDAC plays a crucial role in regulating an intimate dichotomy between cell survival and cell death, characterizing health and diseases . An important first step toward understanding how alteration in VDAC function impacts mitochondrial function is to characterize the structure‐dependent transport characteristics of VDAC across OMM in a solution of multiple ionic species of different ion sizes.…”