VDAC Modulation of Cancer Metabolism: Advances and Therapeutic Challenges

Abstract

Most anionic metabolites including respiratory substrates, glycolytic adenosine triphosphate (ATP), and small cations that enter mitochondria, and mitochondrial ATP moving to the cytosol, cross the outer mitochondrial membrane (OMM) through voltage dependent anion channels (VDAC). The closed states of VDAC block the passage of anionic metabolites, and increase the flux of small cations, including calcium. Consequently, physiological or pharmacological regulation of VDAC opening, by conditioning the magnitude of both anion and cation fluxes, is a major contributor to mitochondrial metabolism. Tumor cells display a pro-proliferative Warburg phenotype characterized by enhanced aerobic glycolysis in the presence of partial suppression of mitochondrial metabolism. The heterogeneous and flexible metabolic traits of most human tumors render cells able to adapt to the constantly changing energetic and biosynthetic demands by switching between predominantly glycolytic or oxidative phenotypes. Here, we describe the biological consequences of changes in the conformational state of VDAC for cancer metabolism, the mechanisms by which VDAC-openers promote cancer cell death, and the advantages of VDAC opening as a valuable pharmacological target. Particular emphasis is given to the endogenous regulation of VDAC by free tubulin and the effects of VDAC-tubulin antagonists in cancer cells. Because of its function and location, VDAC operates as a switch to turn-off mitochondrial metabolism (closed state) and increase aerobic glycolysis (pro-Warburg), or to turn-on mitochondrial metabolism (open state) and decrease glycolysis (anti-Warburg). A better understanding of the role of VDAC regulation in tumor progression is relevant both for cancer biology and for developing novel cancer chemotherapies.

A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay

“…ATP deficiency can be caused by defects in transport of ATP generated in the mitochondrial matrix into the cytoplasm, which is mediated by adenine nucleotide translocase (ANT) family proteins and voltage-dependent anion channels (VDACs). 40 , 41 We examined the expression of Slc25a2, a major ANT, and Vdac1, a major VDAC, in mitochondria-enriched protein fractions of Tomm7(D/D) mice; however, we did not find significant changes in their abundance ( Figure S11 ). The bioenergetic dysfunction and the increased oxygen consumption with normal response to oligomycin, a proton transport inhibitor of complex V, suggest that there is a dissociation between proton transport and catalytic activity of complex V. Complex V consists of two rotary motors, the membrane-bound F 0 that mediates proton transport and F 1 that is responsible for ATP synthesis.…”

Small molecules targeting the NADH-binding pocket of VDAC modulate mitochondrial metabolism in hepatocarcinoma cells

“…From a pharmacological perspective, the success of modulating VDAC opening is most likely to occur if the three isoforms are targeted simultaneously. However, VDAC isoform specificity and lack of identifiable druggable sites, have been big obstacles for the development of drugs regulating VDAC [ 32 , 48 ].…”

Ferroptosis: A New Road towards Cancer Management

“…In this way, the Warburg effect can be activated, resulting in cancer cell aerobic glycolysis. Erastin’s ability to control VDAC opening will have a substantial impact on mitochondrial metabolism, according to this study [ 26 ]. An increase in oxidative phosphorylation will lead to an increase in ROS generation and a reversal of the Warburg phenotype, which is associated with aerobic glycolysis.…”