VDAC isoforms in mammals

Messina, Angela; Reina, Simona; Guarino, Francesca; Pinto, Vito De

doi:10.1016/j.bbamem.2011.10.005

Cited by 224 publications

(232 citation statements)

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“…Three isoforms of VDAC are found in mammals: VDAC1, VDAC2, and VDAC3 (24). Although VDAC1 was identified by mass spectroscopy and Western blot as binding to the itraconazole probe, we wanted to assess whether this binding was isoform specific.…”

Section: Design and Synthesis Of A Photoaffinity Probe Of Itraconazolmentioning

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: Design and Synthesis Of A Photoaffinity Probe Of Itraconazolmentioning

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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“…It is involved primarily in conductance of ions and molecules up to ϳ5 kDa across the outer mitochondrial membrane (1)(2)(3). Interest in the function and regulation of this protein, initiated by its involvement in mitochondria-mediated apoptosis, has expanded further due to its remarkable conservation across eukaryotes (4). Furthermore, it plays a key role in regulating conductance of calcium, ATP, NADH, metabolites etc., voltage-dependent switch in ion conductance, and hexokinase binding (5-7).…”

mentioning

confidence: 99%

“…1A) (4,13,14). Although hVDAC-1 is the primary channel protein involved in anion transport and cellular apoptosis (10), knock-out strains of hVDAC-2 are not viable (15), indicating other critical roles for the isoform 2 that is present only in mammals (15).…”

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confidence: 99%

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Modulation of Human Mitochondrial Voltage-dependent Anion Channel 2 (hVDAC-2) Structural Stability by Cysteine-assisted Barrel-lipid Interactions

Maurya¹,

Mahalakshmi

2013

Journal of Biological Chemistry

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Background: Human VDAC isoform 2 is crucial for apoptosis regulation and cell survival. Results: Cys-less mutant displays significantly lowered unfolding free energy despite greater barrel rigidity. Conclusion: Cysteine residues are key contributors of strong barrel-lipid interactions; hVDAC-2 also requires packing defects in the lipid system to remain stably refolded. Significance: Cys-mediated VDAC-2-lipid interactions may contribute to its anti-apoptotic function.

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“…VDAC1 is the most abundant in cells and is the best characterized of the VDAC isoforms [Messina et al, 2011;Shoshan-Barmatz and Ben-Hail, 2012]. Therefore, for the purposes of this review we will only consider VDAC1 and refer to the protein simply as VDAC.…”

Section: Tubulin Dimers Bind the Mitochondrial Outer Membrane Vdacmentioning

confidence: 99%

Fueled by microtubules: Does tubulin dimer/polymer partitioning regulate intracellular metabolism?

et al. 2012

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Microtubules (MTs) or their subunits, tubulin dimers, interact with multiple components that contribute to intracellular metabolic pathways. MTs are required for insulin-dependent transport of glucose transporter 4 to the plasma membrane, they bind most glycolytic enzymes and are required for translation of the mRNA encoding hypoxia inducible factor-1a. Tubulin dimers bind the voltage-dependent anion channel of the mitochondrial outer membrane; this channel functions in metabolite transport in and out of mitochondria. We hypothesize that tubulin partitioning between dimer and polymer pools regulates multiple steps in metabolism, where metabolic output is greatest when both tubulin dimers and MT polymers are present and reduced by drug treatments that disrupt this normal balance. Experimental evidence from these drug-induced changes in tubulin dimer/polymer partitioning supports our model for several metabolic steps. Signal transduction pathways that stabilize or destabilize MTs can shift the normal ratio between unpolymerized and polymerized tubulin dimers, and one downstream consequence of this shift in tubulin partitioning could be a change in metabolic output. V C 2012 Wiley Periodicals, Inc Key Words: glycolysis, oxidative phosphorylation, glucose transport, voltage-dependent anion channel, tubulin IntroductionT he microtubule (MT) cytoskeleton has well-characterized roles in cell polarity, motility, mitosis, and vesicle traffic. The dynamic turnover of MTs is critical to most of these processes, allowing the cell to reorganize an array of MTs rapidly for specific functions. Here we posit an additional role for MTs in regulating metabolic processes and propose that metabolism is greatest when both MTs and their tubulin subunits are present in cells. Disruption of this normal balance, to either inhibit or promote MT polymerization, is expected to decrease metabolic output. Our hypothesis predicts that chemotherapies that stabilize or destabilize MTs will significantly impact metabolic pathways and reduce ATP levels. Importantly, even a small decrease in ATP production can slow cell proliferation. For example, a 19% decrease in ATP production was sufficient to induce senescence in mouse embryo fibroblasts [Kondoh et al., 2005], indicating that even a relatively small contribution of the MT cytoskeleton to metabolic output could have a significant impact on cell fate.The metabolic components and pathways we consider here include glucose transporters (GLUTs), glycolysis, the pentose phosphate pathway (PPP), and mitochondrial oxidative phosphorylation. Glucose enters cells through glucose transporters called GLUTs; the concentration of GLUTs at the plasma membrane can be regulated by insulin and requires trafficking of GLUT-containing vesicles along MTs to reach the plasma membrane. Within the cytoplasm, glucose is broken down to pyruvate during glycolysis, yielding ATP and NADH. Several intermediate products of glucose breakdown, including glucose-6-phosphate (G6P) and glyceraldehyde-3-phosphate (GAP), can also ...

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VDAC isoforms in mammals

Cited by 224 publications

References 72 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

Modulation of Human Mitochondrial Voltage-dependent Anion Channel 2 (hVDAC-2) Structural Stability by Cysteine-assisted Barrel-lipid Interactions

Fueled by microtubules: Does tubulin dimer/polymer partitioning regulate intracellular metabolism?

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