Voltage-dependent Anion Channels Modulate Mitochondrial Metabolism in Cancer Cells

Maldonado, Eduardo N.; Sheldon, Kely L.; DeHart, David N.; Patnaik, Jyoti; Manevich, Yefim; Townsend, Danyelle M.; Bezrukov, Sergey M.; Rostovtseva, Tatiana K.; Lemasters, John J.

doi:10.1074/jbc.m112.433847

Cited by 221 publications

(230 citation statements)

References 49 publications

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“…More recently it has become clear that the permeability of the OMM is actually regulated by the channels that transport these molecules, the VDACs (40). In 1979 it was predicted that these channels would be involved in regulating mitochondrial metabolism (41), and numerous studies in the ensuing decades have proven this prediction to be true (42)(43)(44)(45)(46). The name of the channel is somewhat misleading, because although it originally was thought to be anion selective, VDAC also has been shown to transport cations such as calcium and numerous small metabolites including ATP, ADP, NADH, pyruvate, and others (47,48).…”

Section: Discussionmentioning

confidence: 99%

Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells

Head

Shi

Zhao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

111

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Itraconazole, a clinically used antifungal drug, was found to possess potent antiangiogenic and anticancer activity that is unique among the azole antifungals. Previous mechanistic studies have shown that itraconazole inhibits the mechanistic target of rapamycin (mTOR) signaling pathway, which is known to be a critical regulator of endothelial cell function and angiogenesis. However, the molecular target of itraconazole that mediates this activity has remained unknown. Here we identify the major target of itraconazole in endothelial cells as the mitochondrial protein voltage-dependent anion channel 1 (VDAC1), which regulates mitochondrial metabolism by controlling the passage of ions and small metabolites through the outer mitochondrial membrane. VDAC1 knockdown profoundly inhibits mTOR activity and cell proliferation in human umbilical vein cells (HUVEC), uncovering a previously unknown connection between VDAC1 and mTOR. Inhibition of VDAC1 by itraconazole disrupts mitochondrial metabolism, leading to an increase in the cellular AMP:ATP ratio and activation of the AMP-activated protein kinase (AMPK), an upstream regulator of mTOR. VDAC1-knockout cells are resistant to AMPK activation and mTOR inhibition by itraconazole, demonstrating that VDAC1 is the mediator of this activity. In addition, another known VDAC-targeting compound, erastin, also activates AMPK and inhibits mTOR and proliferation in HUVEC. VDAC1 thus represents a novel upstream regulator of mTOR signaling in endothelial cells and a promising target for the development of angiogenesis inhibitors.

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Section: Discussionmentioning

confidence: 99%

Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells

Head

Shi

Zhao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

111

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“…24 Erastin can enhance oxidative mitochondrial metabolism and limit aerobic glycolysis by disrupting the interaction between VDAC and tubulin in human liver cancer cells (e.g., HepG2), suggesting a potential role of energy metabolism and cytoskeleton in the modification of ferroptosis. 25 Ras: Erastin exhibits gene-selective lethality in Ras-mutant cells, including H-Ras-mutant engineered cells, N-Rasmutant HT1080 cells, and K-Ras-mutant Calu-1 cells. 4 However, induction of ferroptosis may exist in a both Rasdependent and -independent manner.…”

Section: Molecular Biologymentioning

confidence: 99%

Ferroptosis: process and function

et al. 2016

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Ferroptosis is a recently recognized form of regulated cell death. It is characterized morphologically by the presence of smaller than normal mitochondria with condensed mitochondrial membrane densities, reduction or vanishing of mitochondria crista, and outer mitochondrial membrane rupture. It can be induced by experimental compounds (e.g., erastin, Ras-selective lethal small molecule 3, and buthionine sulfoximine) or clinical drugs (e.g., sulfasalazine, sorafenib, and artesunate) in cancer cells and certain normal cells (e.g., kidney tubule cells, neurons, fibroblasts, and T cells). Activation of mitochondrial voltage-dependent anion channels and mitogen-activated protein kinases, upregulation of endoplasmic reticulum stress, and inhibition of cystine/glutamate antiporter is involved in the induction of ferroptosis. This process is characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS) derived from iron metabolism and can be pharmacologically inhibited by iron chelators (e.g., deferoxamine and desferrioxamine mesylate) and lipid peroxidation inhibitors (e.g., ferrostatin, liproxstatin, and zileuton). Glutathione peroxidase 4, heat shock protein beta-1, and nuclear factor erythroid 2-related factor 2 function as negative regulators of ferroptosis by limiting ROS production and reducing cellular iron uptake, respectively. In contrast, NADPH oxidase and p53 (especially acetylation-defective mutant p53) act as positive regulators of ferroptosis by promotion of ROS production and inhibition of expression of SLC7A11 (a specific light-chain subunit of the cystine/glutamate antiporter), respectively. Misregulated ferroptosis has been implicated in multiple physiological and pathological processes, including cancer cell death, neurotoxicity, neurodegenerative diseases, acute renal failure, drug-induced hepatotoxicity, hepatic and heart ischemia/reperfusion injury, and T-cell immunity. In this review, we summarize the regulation mechanisms and signaling pathways of ferroptosis and discuss the role of ferroptosis in disease.

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“…The main limitation to experimental studies of the sequence-function relationships for the tubulin CTTs is the difficulty of determining the dynamics and conformational ensembles of the intrinsically disordered CTTs. In addition to their important functions involving interactions with motor proteins and other microtubule-associated proteins, tubulin CTTs appear to play a role in regulating permeability of the mitochondrial voltage-dependent anion channel (VDAC) (13)(14)(15)(16). 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.…”

Section: Introductionmentioning

confidence: 99%

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

Rostovtseva

Gurnev

Hoogerheide

et al. 2018

Journal of Biological Chemistry

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The microtubule protein tubulin is a heterodimer comprising / subunits, in which each subunit features multiple isotypes in vertebrates. For example, seven -tubulin and eight -tubulin isotypes in the human tubulin gene family vary mostly in the length and primary sequence of the disordered anionic C-terminal tails (CTTs). The biological reason for such sequence diversity remains a topic of vigorous enquiry. Here, we demonstrate that it may be a key feature of tubulin's role in regulation of the permeability of the mitochondrial outer membrane voltagedependent anion channel (VDAC). Using recombinant yeast /-tubulin constructs with -CTTs, -CTTs, or both from various human tubulin isotypes, we probed their interactions with VDAC reconstituted into planar lipid bilayers. A comparative study of the blockage kinetics revealed that either -CTTs or -CTTs block VDAC pore and that the efficiency of blockage by individual CTTs spans two orders of magnitude, depending on the CTT isotype.-Tubulin constructs, notably 3, blocked VDAC most effectively. We quantitatively describe these experimental results using a physical model that accounts only for the number and distribution of charges in the CTT, and not for the interactions between specific residues on the CTT and VDAC pore. Based on these results, we speculate that the effectiveness of VDAC regulation by tubulin depends on the predominant tubulin isotype in a cell. Consequently, the fluxes of ATP/ADP http://www.jbc.org/cgi

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Voltage-dependent Anion Channels Modulate Mitochondrial Metabolism in Cancer Cells

Abstract: Background: Metabolites generating mitochondrial membrane potential (⌬⌿) enter through voltage-dependent anion channels (VDAC). Results: VDAC3 contributed to ⌬⌿ formation more than VDAC1/2. VDAC3 knockdown decreased ATP and NADH/NAD ϩ .

Cited by 221 publications

References 49 publications

Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells

Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells

Ferroptosis: process and function

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

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