Novel Compounds Targeting the Mitochondrial Protein VDAC1 Inhibit Apoptosis and Protect against Mitochondrial Dysfunction

Abstract

Edited by Linda SpremulliApoptosis is thought to play a critical role in several pathological processes, such as neurodegenerative diseases (i.e. Parkinson's and Alzheimer's diseases) and various cardiovascular diseases. Despite the fact that apoptotic mechanisms are well defined, there is still no substantial therapeutic strategy to stop or even slow this process. Thus, there is an unmet need for therapeutic agents that are able to block or slow apoptosis in neurodegenerative and cardiovascular diseases. The outer mitochondrial membrane protein voltage-dependent anion channel 1 (VDAC1) is a convergence point for a variety of cell survival and death signals, including apoptosis. Recently, we demonstrated that VDAC1 oligomerization is involved in mitochondrion-mediated apoptosis. Thus, VDAC1 oligomerization represents a prime target for agents designed to modulate apoptosis. Here, high-throughput compound screening and medicinal chemistry were employed to develop compounds that directly interact with VDAC1 and prevent VDAC1 oligomerization, concomitant with an inhibition of apoptosis as induced by various means and in various cell lines. The compounds protected against apoptosis-associated mitochondrial dysfunction, restoring dissipated mitochondrial membrane potential, and thus cell energy and metabolism, decreasing reactive oxidative species production, and preventing detachment of hexokinase bound to mitochondria and disruption of intracellular Ca 2؉ levels. Thus, this study describes novel drug candidates with a defined mechanism of action that involves inhibition of VDAC1 oligomerization, apoptosis, and mitochondrial dysfunction. The compounds VBIT-3 and VBIT-4 offer a therapeutic strategy for treating different diseases associated with enhanced apoptosis and point to VDAC1 as a promising target for therapeutic intervention.Mitochondria play crucial roles in cellular energy generation and metabolism, maintenance of the cell redox potential, calcium homeostasis, pH control and fatty acid oxidation, cell signaling, proliferation, differentiation, aging, and death (1). It is therefore not surprising that mitochondrial dysfunction is associated with various human diseases (1, 2).Located at the outer mitochondrial membrane (OMM), 2 the voltage-dependent anion channel (VDAC) serves as a mitochondrial gatekeeper. Three VDAC isoforms have been discovered (3), but only for VDAC1 is there a complete set of structural and functional information available. VDAC1 controls the metabolic and energy cross-talk between mitochondria and the rest of the cell, mediating the fluxes of ions, nucleotides, and other metabolites across the OMM (4 -7).

Commentary: Synthetic Ubiquinones Specifically Bind to Mitochondrial Voltage-Dependent Anion Channel 1 (VDAC1) in Saccharomyces cerevisiae Mitochondria

“…Thus, the results presented by Murai and colleagues place VDAC1 as an obvious “gate” that may indirectly regulate the PTP (an inner membrane event) under certain experimental conditions. This proposal is also substantiated by recent reports showing that a new set of VDAC1 effectors reduce matrix Ca 2+ , oxidative stress and mitochondrial transmembrane potential dissipation in mammalian mitochondria (Ben-Hail et al, 2016). Consequently, VDAC1 targeting may still constitute a cogent strategy to control PTP opening and this possibility should be considered in more detail.…”

Novel function of ceramide for regulation of mitochondrial ATP release in astrocytes

“…Malfunction of mitochondria and dysregulated VDAC1 have been implicated in many neurodegenerative diseases, including AD, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia (35)(36)(37)(38)(39)(40)(41)(42). In AD, Aβ has been shown to bind to VDAC1, reduce ATP levels, and cause mitochondrial fragmentation during early stages of the disease (35,43,44).…”

Establishment of a Temperature-Sensitive Model of Oncogene-Induced Senescence in Angiosarcoma Cells

“…The increase in BAD phosphorylation suggests that it is required for alleviating the oncogene-induced stress. VDAC1 appears to be upregulated by temperature shift in both MS1 and SVR, with a more pronounced effect in the MS1 (Figure 5), implying that ras might downregulate VDAC1 under conditions of stress [44,45]. p53 is rapidly phosphorylated in SVR cells upon shift to 39 • C ( Figure 5) and it is well known that phosphorylated p53 translocates to the mitochondria and may mediate apoptosis [46].…”

“…Of note, the mitochondrial protein BAD is phosphorylated at Ser 112 only in the ras transformed SVR cells, compared with parental MS1 cells, and is decreased upon temperature shift to 39 • C ( Figure 5). BAD is phosphorylated at Ser 112 which inactivates the mitochondrial apoptosis associated with BAD heterodimerization [45]. The increase in BAD phosphorylation suggests that it is required for alleviating the oncogene-induced stress.…”