VDAC Regulation: A Mitochondrial Target to Stop Cell Proliferation

Abstract

Cancer metabolism is emerging as a chemotherapeutic target. Enhanced glycolysis and suppression of mitochondrial metabolism characterize the Warburg phenotype in cancer cells. The flux of respiratory substrates, ADP, and Pi into mitochondria and the release of mitochondrial ATP to the cytosol occur through voltage-dependent anion channels (VDACs) located in the mitochondrial outer membrane. Catabolism of respiratory substrates in the Krebs cycle generates NADH and FADH2 that enter the electron transport chain (ETC) to generate a proton motive force that maintains mitochondrial membrane potential (ΔΨ) and is utilized to generate ATP. The ETC is also the major cellular source of mitochondrial reactive oxygen species (ROS). αβ-Tubulin heterodimers decrease VDAC conductance in lipid bilayers. High constitutive levels of cytosolic free tubulin in intact cancer cells close VDAC decreasing mitochondrial ΔΨ and mitochondrial metabolism. The VDAC–tubulin interaction regulates VDAC opening and globally controls mitochondrial metabolism, ROS formation, and the intracellular flow of energy. Erastin, a VDAC-binding molecule lethal to some cancer cell types, and erastin-like compounds identified in a high-throughput screening antagonize the inhibitory effect of tubulin on VDAC. Reversal of tubulin inhibition of VDAC increases VDAC conductance and the flux of metabolites into and out of mitochondria. VDAC opening promotes a higher mitochondrial ΔΨ and a global increase in mitochondrial metabolism leading to high cytosolic ATP/ADP ratios that inhibit glycolysis. VDAC opening also increases ROS production causing oxidative stress that, in turn, leads to mitochondrial dysfunction, bioenergetic failure, and cell death. In summary, antagonism of the VDAC–tubulin interaction promotes cell death by a “double-hit model” characterized by reversion of the proproliferative Warburg phenotype (anti-Warburg) and promotion of oxidative stress.

Erastin Reverses ABCB1-Mediated Docetaxel Resistance in Ovarian Cancer

“…The accumulation of rhodamine 123 confirmed that erastin significantly antagonized the drug-efflux function of ABCB1. Moreover, it has been reported that the safety of erastin in xenograft modes is acceptable (43,44). Inhibition of SLC7A11 by erastin also increased the sensitivity of cisplatin in cancer cells (19,45), suggesting the combination of erastin and chemotherapeutical reagents can be sufficient for cancer therapy.…”

Membrane Nanoparticles Derived from ACE2-rich Cells Block SARS-CoV-2 Infection

“…Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis discovered six signaling pathways (Table S2), i.e., cGMP-PKG signaling pathway, NOD-like receptor signaling pathway, calcium signaling pathway, cholesterol metabolism, necroptosis, and ferroptosis, which were influenced by SARS-CoV-2 S1 (Figure 4b). The up-regulation of VDAC1-3, three mitochondrial membrane porins involved in bioenergetic failure and cell apoptosis, [19][20] were attributable. In the presence of HEK-293T-hACE2 NPs, the imbalance of VDAC1-3 was corrected ( Figure 4c), and the number of changed proteins was reduced to thirty-one (Table S3), by which no signaling pathway was enriched by KEGG yet.…”

Ferroptosis and Cancer: Mitochondria Meet the “Iron Maiden” Cell Death

“…Although VDACs have been largely considered constitutively open, recent studies show that VDACs conductance capacity is inhibited by intracellular free tubulin abundance [ 181 ]. In preclinical models of osteosarcoma, microtubule-destabilizing agents increase cytoplasmic free tubulin causing a decrease of ΔΨ m [ 182 ].…”