Regulation of mitochondrial function by voltage dependent anion channels in ethanol metabolism and the Warburg effect

Lemasters, John J.; Holmuhamedov, Ekhson; Czerny, C.; Zhong, Zhi; Maldonado, Eduardo N.

doi:10.1016/j.bbamem.2011.11.034

Cited by 42 publications

(32 citation statements)

References 83 publications

(120 reference statements)

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“…Substrates entering the outer mitochondrial membrane pass through voltage-dependent anion channels (VDACs; Lemasters and Holmuhamedov, 2006;Lemasters et al, 2012;Holmuhamedov et al, 2012). During normal metabolism, it is assumed that VDACs are open, supporting the commonly accepted paradigm that small molecular weight molecules pass through the outer mitochondrial membrane freely.…”

Section: Discussionmentioning

confidence: 99%

Paradoxical anaerobism in desert pupfish

Heuton

Ayala

Burg

et al. 2015

Journal of Experimental Biology

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In order to estimate metabolic demands of desert pupfish for conservation purposes, we measured oxygen consumption in fish acclimated to the ecologically relevant temperatures of 28 or 33°C. For these experiments, we used fish derived from a refuge population of Devils Hole pupfish (Cyprinodon diabolis). Measurement of routine oxygen consumption (V O2,routine ) revealed some 33°C-acclimated fish (10% of 295 assayed fish) periodically exhibited periods of no measurable oxygen consumption despite available ambient oxygen tensions that were above the critical P O2 . We call this phenomenon paradoxical anaerobism. The longest observed continuous bout with no oxygen consumption was 149 min, although typical bouts were much shorter. Fish maintained normal posture and ventilation rate (>230 ventilations per minute) during paradoxical anaerobism. Fish rarely demonstrated a compensatory increase in oxygen use following a period of paradoxical anaerobism. In contrast, only one out of 262 sampled fish acclimated at 28°C spontaneously demonstrated paradoxical anaerobism. Muscle lactate concentration was not elevated during periods of paradoxical anaerobism. However, the amount of ethanol released by the 33°C-acclimated fish was 7.3 times greater than that released by the 28°C acclimation group, suggesting ethanol may be used as an alternative end product of anaerobic metabolism. Exposure to exogenous ethanol, in concentrations as low as 0.1%, produced periods of paradoxical anaerobism even in 28°C-acclimated fish.

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Section: Discussionmentioning

confidence: 99%

Paradoxical anaerobism in desert pupfish

Heuton

Ayala

Burg

et al. 2015

Journal of Experimental Biology

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“…The primary cellular function of VDAC is to regulate mitochondrial function by controlling the movement of ions and small metabolites across the OMM (25,26). Because of the central role of mitochondria in a myriad of cellular processes, we reasoned that there is likely to be a pathway by which mitochondrial function is connected to mTOR activity; however, this link has not been demonstrated directly (27).…”

Section: Knockdown Of Vdac1 In Huvec Phenocopies the Effects Of Itracmentioning

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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“…As such, VDAC appears to be a convergence point for a variety of cell survival and cell death signals. Accordingly, several recent reviews have focused on VDAC as being an essential player in apoptosis [2,7], on novel VDAC functions [8], on VDAC structure and function [9,10], on the location and function of VDAC in the sarcoplasmic reticulum membrane [11], and on the modulation of VDAC and its contribution to the roles played by mitochondria in cell life and death [12][13][14], as well as on the role of VDAC in cancer [5,6], in hypoxia [15] and in the Warburg effect [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

The mitochondrial voltage-dependent anion channel 1 in tumor cells

Shoshan‐Barmatz

Ben-Hail

Admoni

et al. 2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

214

254

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VDAC1 is found at the crossroads of metabolic and survival pathways. VDAC1 controls metabolic cross-talk between mitochondria and the rest of the cell by allowing the influx and efflux of metabolites, ions, nucleotides, Ca2+ and more. The location of VDAC1 at the outer mitochondrial membrane also enables its interaction with proteins that mediate and regulate the integration of mitochondrial functions with cellular activities. As a transporter of metabolites, VDAC1 contributes to the metabolic phenotype of cancer cells. Indeed, this protein is over-expressed in many cancer types, and silencing of VDAC1 expression induces an inhibition of tumor development. At the same time, along with regulating cellular energy production and metabolism, VDAC1 is involved in the process of mitochondria-mediated apoptosis by mediating the release of apoptotic proteins and interacting with anti-apoptotic proteins. The engagement of VDAC1 in the release of apoptotic proteins located in the inter-membranal space involves VDAC1 oligomerization that mediates the release of cytochrome c and AIF to the cytosol, subsequently leading to apoptotic cell death. Apoptosis can also be regulated by VDAC1, serving as an anchor point for mitochondria-interacting proteins, such as hexokinase (HK), Bcl2 and Bcl-xL, some of which are also highly expressed in many cancers. By binding to VDAC1, HK provides both a metabolic benefit and apoptosis-suppressive capacity that offer the cell a proliferative advantage and increase its resistance to chemotherapy. Thus, these and other functions point to VDAC1 as an excellent target for impairing the re-programed metabolism of cancer cells and their ability to evade apoptosis. Here, we review current evidence pointing to the function of VDAC1 in cell life and death, and highlight these functions in relation to both cancer development and therapy. In addressing the recently solved 3D structures of VDAC1, this review will point to structure-function relationships of VDAC as critical for deciphering how this channel can perform such a variety of roles, all of which are important for cell life and death. Finally, this review will also provide insight into VDAC function in Ca2+ homeostasis, protection against oxidative stress, regulation of apoptosis and involvement in several diseases, as well as its role in the action of different drugs. We will discuss the use of VDAC1-based strategies to attack the altered metabolism and apoptosis of cancer cells. These strategies include specific siRNA able to impair energy and metabolic homeostasis, leading to arrested cancer cell growth and tumor development, as well VDAC1-based peptides that interact with anti-apoptotic proteins to induce apoptosis, thereby overcoming the resistance of cancer cell to chemotherapy. Finally, small molecules targeting VDAC1 can induce apoptosis. VDAC1 can thus be considered as standing at the crossroads between mitochondrial metabolite transport and apoptosis and hence represents an emerging cancer drug target. This article is part of a Special ...

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Regulation of mitochondrial function by voltage dependent anion channels in ethanol metabolism and the Warburg effect

Cited by 42 publications

References 83 publications

Paradoxical anaerobism in desert pupfish

Paradoxical anaerobism in desert pupfish

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

The mitochondrial voltage-dependent anion channel 1 in tumor cells

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