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ROS production by Wt and Vdac1 −/− MEF. a Representative electron micrographs of mitochondria of Wt and Vdac1 −/− MEF incubated in normoxia (Nx) or hypoxia 1 % O 2 (Hx) for 72 h. b Immunofluorescence to COX4-2 and COX7A1 in Wt and Vdac1 −/− MEF in Hx for 72 h. c Respiratory control of Wt and Vdac1 −/− MEF. Oxygen Consumption Rate (OCR) was measured in real time with a Seahorse XF bioenergetic system for Wt and Vdac1 −/− MEF in Nx or Hx. ΔOCR was calculated from at least four measurements before and after treatment with rotenone at 1 μM. d Quantitative measurement of ROS production was done by staining with the fluorescent probe 2', 7'-dichlorofluorescin diacetate (DCFH-DA) followed by flow cytometry. These graphs are representative of four different experiments; p < 0.02, significant difference to Wt MEF in normoxia (Nx). e Wt and Vdac1 −/− MEF seeded at the same density were incubated in Nx for 3 days in the presence of N-acetyl-l-cysteine (NAC, up to 1 mM). Mean ± SEM is representative of two independent experiments carried out in duplicate. f Wt and Vdac1 −/− MEF were incubated in Hx for 72 h in the absence (−) or presence (+) of NAC (1 mM) and cell lysates were analyzed by immunoblotting for P-ERK. ARD1 was used as a loading control. g Wt (+) and Vdac1 −/− (−) MEF were incubated in Nx for 24 h in the absence (−NAC) or presence (+NAC) of NAC (1 mM) and cell lysates were analyzed by immunoblotting for HIF-1α. ARD1 was used as a loading control. h Wt and Vdac1 −/− MEF were incubated in Nx for 3 days in the presence of H 2 O 2 (up to 100 μM). Mean ± SEM is representative of two independent experiments carried out in duplicate. i Wt (+) and Vdac1 −/− (−) MEF were incubated in Nx or Hx for 72 h and cell lysates were analyzed by immunoblotting to GPX7. ARD1 was the loading control
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Mitochondria are more than just the powerhouse of cells; they dictate if a cell dies or survives. Mitochondria are dynamic organelles that constantly undergo fusion and fission in response to environmental conditions. We showed previously that mitochondria of cells in a low oxygen environment (hypoxia) hyperfuse to form enlarged or highly interconn...
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... online version of the article contains a data supplement Additional file 2: Figure S1 and Additional file 7: Figure S2 show detailed data related to the microarray analysis. Additional file 8: Figure S3 shows expression of COX4- 2. Additional file 9: Figure S4 shows the ROS status. Additional file 10: Figure S5 shows expression of GPX7 and the effect of ebselen. ...
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... Vdac1 −/− MEF defects in expression of mRNAs implicated in mitochondrial respiration (Additional file 7: Figure S2), including complexes I, III, IV, and V, we hypothesized that these defects could generate ROS, which could then stabilize HIF-1α [16][17][18]. Mitochondria of Wt MEF in normoxia appeared as a tubular network with normal cristae (Fig. 3a), whereas hypoxic Wt MEF showed en- larged mitochondria with a modified organization of cristae, as reported [14]. The mitochondria of Vdac1 −/− MEF were enlarged, but in both normoxia and hypoxia. In addition, hypoxic mitochondria of Vdac1 −/− MEF showed two different populations of mitochondria. One (around 50 %; data not shown) ...
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... reached their bioenergetic limit. To explain the abundance of cristae and higher res- piration in hypoxia in Vdac1 −/− MEF, we investigated the expression of cytochrome oxidase (COX). The level of COX4-1, was slightly decreased in hypoxia in both cell lines (data not shown), whereas COX4-2 showed a marked increase in hypoxia in both cell lines (Fig. 3b), as described [21]. A higher level of COX4-2 and COX7A1 (more dots) in Vdac1 −/− MEF in hypoxia than in Wt MEF was de- tected ( Fig. 3b, Additional file 8: Figure S3A). Blockade of COX4-2 expression and of proliferation of Vdac1 −/− MEF in hypoxia in the presence of PD184352, a specific in- hibitor of MEK, suggested that COX4-2 could ...
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... the expression of cytochrome oxidase (COX). The level of COX4-1, was slightly decreased in hypoxia in both cell lines (data not shown), whereas COX4-2 showed a marked increase in hypoxia in both cell lines (Fig. 3b), as described [21]. A higher level of COX4-2 and COX7A1 (more dots) in Vdac1 −/− MEF in hypoxia than in Wt MEF was de- tected ( Fig. 3b, Additional file 8: Figure S3A). Blockade of COX4-2 expression and of proliferation of Vdac1 −/− MEF in hypoxia in the presence of PD184352, a specific in- hibitor of MEK, suggested that COX4-2 could regulate proliferation in hypoxia through the activation of ERK (Additional file 8: Figure S3B). However, while silencing of COX4-2 and ...
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... level of COX4-1, was slightly decreased in hypoxia in both cell lines (data not shown), whereas COX4-2 showed a marked increase in hypoxia in both cell lines (Fig. 3b), as described [21]. A higher level of COX4-2 and COX7A1 (more dots) in Vdac1 −/− MEF in hypoxia than in Wt MEF was de- tected ( Fig. 3b, Additional file 8: Figure S3A). Blockade of COX4-2 expression and of proliferation of Vdac1 −/− MEF in hypoxia in the presence of PD184352, a specific in- hibitor of MEK, suggested that COX4-2 could regulate proliferation in hypoxia through the activation of ERK (Additional file 8: Figure S3B). ...
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... higher level of COX4-2 and COX7A1 (more dots) in Vdac1 −/− MEF in hypoxia than in Wt MEF was de- tected ( Fig. 3b, Additional file 8: Figure S3A). Blockade of COX4-2 expression and of proliferation of Vdac1 −/− MEF in hypoxia in the presence of PD184352, a specific in- hibitor of MEK, suggested that COX4-2 could regulate proliferation in hypoxia through the activation of ERK (Additional file 8: Figure S3B). However, while silencing of COX4-2 and COX7A1 with siRNA diminished sub- stantially the respective mRNA levels, only silencing of COX7A1 decreased proliferation in Vdac1 −/− MEF with- out modifying apoptosis (data not shown). ...
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... of complex I with rotenone in Wt MEF markedly decreased basal respiration, suggesting a nor- mal complex I activity in normoxia (Fig. 3c). Inhibition with rotenone did not affect complex I activity in hyp- oxia as it is known that its activity is already reduced in hypoxia [22]. However, rotenone did not modify the OCR of Vdac1 −/− MEF, which suggests that the complex I activity was already diminished. We then quantified the levels of ROS (Fig. 3d). We found a strong ...
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... complex I activity in normoxia (Fig. 3c). Inhibition with rotenone did not affect complex I activity in hyp- oxia as it is known that its activity is already reduced in hypoxia [22]. However, rotenone did not modify the OCR of Vdac1 −/− MEF, which suggests that the complex I activity was already diminished. We then quantified the levels of ROS (Fig. 3d). We found a strong correl- ation between the inactivation of complex I and ROS production. In addition, using a cuvette-based Amplex UltraRed assay for mitochondrial production of H 2 O 2 , Vdac1 −/− MEF mitochondria produced more H 2 O 2 than did the Wt MEF (Additional file 9: Figure S4A). N- acetyl-L-cysteine restored proliferation ...
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... control. h Wt and Vdac1 −/− MEF were incubated in Nx for 3 days in the presence of H 2 O 2 (up to 100 μM). Mean ± SEM is representative of two independent experiments carried out in duplicate. i Wt (+) and Vdac1 −/− (−) MEF were incubated in Nx or Hx for 72 h and cell lysates were analyzed by immunoblotting to GPX7. ARD1 was the loading control ( Fig. 3e), decreased P-ERK in hypoxia (Fig. 3f ), and de- creased HIF-1α in normoxia (Fig. 3g). Addition of hydrogen peroxide to Wt MEF decreased proliferation to a level similar to that of Vdac1 −/− MEF (Fig. 3h). The expression of enzymes involved in upstream or downstream transformation of H 2 O 2 including superoxide dismutase 3 (Sod3) and ...
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... incubated in Nx for 3 days in the presence of H 2 O 2 (up to 100 μM). Mean ± SEM is representative of two independent experiments carried out in duplicate. i Wt (+) and Vdac1 −/− (−) MEF were incubated in Nx or Hx for 72 h and cell lysates were analyzed by immunoblotting to GPX7. ARD1 was the loading control ( Fig. 3e), decreased P-ERK in hypoxia (Fig. 3f ), and de- creased HIF-1α in normoxia (Fig. 3g). Addition of hydrogen peroxide to Wt MEF decreased proliferation to a level similar to that of Vdac1 −/− MEF (Fig. 3h). The expression of enzymes involved in upstream or downstream transformation of H 2 O 2 including superoxide dismutase 3 (Sod3) and glutathione peroxidase 7 (Gpx7) were ...
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... 2 O 2 (up to 100 μM). Mean ± SEM is representative of two independent experiments carried out in duplicate. i Wt (+) and Vdac1 −/− (−) MEF were incubated in Nx or Hx for 72 h and cell lysates were analyzed by immunoblotting to GPX7. ARD1 was the loading control ( Fig. 3e), decreased P-ERK in hypoxia (Fig. 3f ), and de- creased HIF-1α in normoxia (Fig. 3g). Addition of hydrogen peroxide to Wt MEF decreased proliferation to a level similar to that of Vdac1 −/− MEF (Fig. 3h). The expression of enzymes involved in upstream or downstream transformation of H 2 O 2 including superoxide dismutase 3 (Sod3) and glutathione peroxidase 7 (Gpx7) were tightly regulated in Vdac1 −/− MEF (Additional ...
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... Vdac1 −/− (−) MEF were incubated in Nx or Hx for 72 h and cell lysates were analyzed by immunoblotting to GPX7. ARD1 was the loading control ( Fig. 3e), decreased P-ERK in hypoxia (Fig. 3f ), and de- creased HIF-1α in normoxia (Fig. 3g). Addition of hydrogen peroxide to Wt MEF decreased proliferation to a level similar to that of Vdac1 −/− MEF (Fig. 3h). The expression of enzymes involved in upstream or downstream transformation of H 2 O 2 including superoxide dismutase 3 (Sod3) and glutathione peroxidase 7 (Gpx7) were tightly regulated in Vdac1 −/− MEF (Additional file 5: Table S4). However, SOD1, SOD2, and SOD3 showed no difference in expression in normoxia (Additional file 10: ...
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... regulated in Vdac1 −/− MEF (Additional file 5: Table S4). However, SOD1, SOD2, and SOD3 showed no difference in expression in normoxia (Additional file 10: Figure S5B) or hypoxia (data not shown) in Wt MEF com- pared to Vdac1 −/− MEF. GPX7, which detoxifies hydro- peroxide substrates, was absent in Vdac1 −/− MEF in both normoxia and hypoxia (Fig. 3i, Additional file 10: Figure S5A). Moreover, ebselen, a mimetic of GPX [23], did not modify HIF-1α stability (Additional file 10: Figure S5B). It decreased slightly the proliferation of Wt MEF, but not Vdac1 −/− MEF (Additional file 10: Figure S5C) and increased slightly the viability of Vdac1 −/− MEF (Additional file 10: Figure S5D), ...
Citations
... Its physiological interaction with HKs allows it to combine glycolysis with oxidative phosphorylation, contributing to the maintenance of proper ATP/ADP levels and the inhibition of apoptosis [28,45,46]. In contrast, the inactivation of VDAC1 gene is enough to cause the collapse of the mitochondrial respiratory system, prompting the cell towards a metabolic rewiring to overcome the mitochondrial failure [47][48][49]. Therefore, VDAC1 behaves as a molecular switch that, if turned off, may have serious consequences for the cell survival. ...
Mitochondrial dysfunction represents one of the most common molecular hallmarks of both sporadic and familial forms of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder caused by the selective degeneration and death of motor neurons. The accumulation of misfolded proteins on and within mitochondria, as observed for SOD1 G93A mutant, correlates with a drastic reduction of mitochondrial respiration and the inhibition of metabolites exchanges, including ADP/ATP and NAD ⁺ /NADH, across the Voltage-Dependent Anion-selective Channel 1 (VDAC1), the most abundant channel protein of the outer mitochondrial membrane. Here, we show that the AAV-mediated upregulation of VDAC1 in the spinal cord of transgenic mice expressing SOD1 G93A completely rescues the mitochondrial respiratory profile. This correlates with the increased activity and levels of key regulators of mitochondrial functions and maintenance, namely the respiratory chain Complex I and the sirtuins (Sirt), especially Sirt3. Furthermore, the selective increase of these mitochondrial proteins is associated with an increase in Tom20 levels, the receptor subunit of the TOM complex. Overall, our results indicate that the overexpression of VDAC1 has beneficial effects on ALS-affected tissue by stabilizing the Complex I-Sirt3 axis.
... [27] clearly explains the importance of hypoxia in cancer cell resistance, our article addresses the issue of metabolism in a hypoxic environment and its therapeutic possibilities. We bring considerable expertise and experience from many years of work using this approach in colon [28,29] and kidney [30] cancers and focus on the critical role of mitochondria [31,32]. ...
Medulloblastoma is a cancerous brain tumor that affects mostly children. Among the four groups defined by molecular characteristics, Group 3, the least well characterized, is also the least favorable, with a survival rate of 50%. Current treatments, based on surgery, radiotherapy, and chemotherapy, are not adequate and the lack of understanding of the different molecular features of Group 3 tumor cells makes the development of effective therapies challenging. In this study, the problem of medulloblastoma is approached from a metabolic standpoint in a low oxygen microenvironment. We establish that Group 3 cells use both the mitochondrial glycerol-3 phosphate (G3PS) and malate-aspartate shuttles (MAS) to produce NADH. Small molecules that target G3PS and MAS show a greater ability to decrease cell proliferation and induce apoptosis specifically of Group 3 cells. In addition, as Group 3 cells show improved respiration in hypoxia, the use of Phenformin, a mitochondrial complex 1 inhibitor, alone or in combination, induced significant cell death. Furthermore, inhibition of the cytosolic NAD+ recycling enzyme lactate dehydrogenase A (LDHA), enhanced the effects of the NADH shuttle inhibitors. In a 3D model using Group 3 human cerebellar organoids, tumor cells also underwent apoptosis upon treatment with NADH shuttle inhibitors. Our study demonstrates metabolic heterogeneity depending on oxygen concentrations and provides potential therapeutic solutions for patients in Group 3 whose tumors are the most aggressive.
... VDAC is important for regulating apoptosis through the interaction with proteins of the Bcl-2 family [69]. VDAC has also been linked to protecting against oxidative stress, where downregulation or absence of VDAC has been shown in numerous studies to increase the production of ROS [70][71][72]. VDAC3 has also been shown to counteract ROS-induced oxidative stress [73]. ...
Although elevated cholesterol and other recognised cardiovascular risk factors are important in the development of coronary artery disease (CAD) and heart attack, the susceptibility of humans to this fatal process is distinct from other animals. Mitochondrial dysfunction of cells in the arterial wall, particularly the endothelium, has been strongly implicated in the pathogenesis of CAD. In this manuscript, we review the established evidence and mechanisms in detail and explore the potential opportunities arising from analysing mitochondrial function in patient-derived cells such as endothelial colony-forming cells easily cultured from venous blood. We discuss how emerging technology and knowledge may allow us to measure mitochondrial dysfunction as a potential biomarker for diagnosis and risk management. We also discuss the “pros and cons” of animal models of atherosclerosis, and how patient-derived cell models may provide opportunities to develop novel therapies relevant for humans. Finally, we review several targets that potentially alleviate mitochondrial dysfunction working both via direct and indirect mechanisms and evaluate the effect of several classes of compounds in the cardiovascular context.
... The strategic localisation of VDAC in the OMM allows it to participate in cell metabolism and cross-talk between the cellular environment outside the mitochondria and the intermembrane space (IMS). VDAC has been found to transport important metabolites including ATP/ADP, NADH, pyruvate and a number of ions (calcium, chloride, potassium, magnesium, sodium), 12,13 and act as a docking site for tubulin, hexokinases, pro-and anti-apoptotic proteins. 14 For example, VDAC1 has a significant role in cell metabolism due to its participation and regulation of energy production via nucleotide transportation. ...
... On the contrary, VDAC3 knock-out is not lethal but VDAC3deficient male mice suffer from infertility since VDAC3 is expressed in the testes. 8,13,22,23 As a result, findings suggest that VDAC3 is evolutionarily different from VDAC1 and VDAC2 and, accordingly, has more isoform-specific roles, namely ROS homoeostasis. 8,15,24 The mitochondrion emits ROS byproducts (superoxide and hydrogen peroxide) from metabolic activities, but at the same time, it has to be protected from them. 25 These by-products accumulate in the IMS since they are produced by the electron transport chain and oxidative phosphorylation (Complex III). ...
Viruses control the host cell by exploiting its molecular machinery to facilitate viral replication and propagation. Understanding different viral mechanisms and biochemical pathways is crucial for finding promising therapeutic solutions to viral infections. The mitochondrion is a vital organelle targeted by various types of viruses. More specifically, viruses interact with the voltage-dependent anion channel (VDAC), a porin protein found in the outer mitochondrial membrane. VDAC controls metabolite flux, regulates reactive oxygen species production, and promotes mitochondrial-mediated apoptosis by releasing pro-apoptotic proteins. Hence, a common pathogenic strategy used by many viruses seems to exploit natural pathways that VDAC regulates. This review aims to address the inhibition and enhancement roles of VDAC in viral pathogenesis and outlines multiple links and interactions between VDAC and viral proteins as potential antiviral targets.
... In mammals, knockout experiments are made more complicated to interpret due to the presence of the other isoforms, which can partially complement the lack of VDAC1. Interestingly, in mouse embryonic fibroblast VDAC1 deletion promotes a partial rearrangement of gene expression that triggers metabolic impairments and the accumulation of reactive oxygen species (ROS) [34], overlapping in part the changes already seen in yeast. Additionally, VDAC1 knockout makes H9c2 cells more susceptible to ROS-induced apoptosis [35], while in chronic myelogenous leukemia-derived cells it correlates with a slight reduction in mitochondrial mass and the hyperpolarization of the mitochondrial membranes [31]. ...
Voltage-Dependent Anion-selective Channel isoform 1 (VDAC1) is the most abundant isoform of the outer mitochondrial membrane (OMM) porins and the principal gate for ions and metabolites to and from the organelle. VDAC1 is also involved in a number of additional functions, such as the regulation of apoptosis. Although the protein is not directly involved in mitochondrial respiration, its deletion in yeast triggers a complete rewiring of the whole cell metabolism, with the inactivation of the main mitochondrial functions. In this work, we analyzed in detail the impact of VDAC1 knockout on mitochondrial respiration in the near-haploid human cell line HAP1. Results indicate that, despite the presence of other VDAC isoforms in the cell, the inactivation of VDAC1 correlates with a dramatic impairment in oxygen consumption and a re-organization of the relative contributions of the electron transport chain (ETC) enzymes. Precisely, in VDAC1 knockout HAP1 cells, the complex I-linked respiration (N-pathway) is increased by drawing resources from respiratory reserves. Overall, the data reported here strengthen the key role of VDAC1 as a general regulator of mitochondrial metabolism.
... Knockout mice with the expression of VDAC1 silenced exhibit sensitivity for transport of ADP in oxidative striated muscles, thus affecting the energy metabolism [51]. Deletion of VDAC1 can generate ROS and induce tumor growth in mouse embryonic fibroblasts [52]. The PINK1/Parkin-mediated mitochondrial autophagy pathway has become a promising strategy for the treatment of PD [31]. ...
Parkinson’s disease (PD) is a neurodegenerative disease second only to Alzheimer’s disease in terms of prevalence. Previous studies have indicated that the occurrence and progression of PD are associated with mitochondrial dysfunction. Mitochondrial dysfunction is one of the most important causes for apoptosis of dopaminergic neurons. Therefore, maintaining the stability of mitochondrial functioning is a potential strategy in the treatment of PD. Voltage-dependent anion channel (VDAC) is the main component in the outer mitochondrial membrane, and it participates in a variety of biological processes. In this review, we focus on the potential roles of VDACs in the treatment of PD. We found that VDACs are involved in PD by regulating apoptosis, autophagy, and ferroptosis. VDAC1 oligomerization, VDACs ubiquitination, regulation of mitochondrial permeability transition pore (mPTP) by VDACs, and interaction between VDACs and α-synuclein (α-syn) are all promising methods for the treatment of PD. We proposed that inhibition of VDAC1 oligomerization and promotion of VDAC1 ubiquitination as an effective approach for the treatment of PD. Previous studies have proven that the expression of VDAC1 has a significant change in PD models. The expression levels of VDAC1 are decreased in the substantia nigra (SN) of patients suffering from PD compared with the control group consisting of normal individuals by using bioinformatics tools. VDAC2 is involved in PD mainly through the regulation of apoptosis. VDAC3 may have a similar function to VDAC1. It can be concluded that the functional roles of VDACs contribute to the therapeutic strategy of PD.
... Cancer-associated hypoxia has been involved with resistance to apoptosis by enhancing the expression of antiapoptotic proteins such as BNIP3/3L, NDRG, MCL1, and NPM1 [73]. Apart from transcriptional reprogramming, it has been shown that hypoxia triggers the proteolytic processing of mitochondrial VDAC1 and a C-terminally truncated form (VDAC1-ΔC) is produced and protects from pharmacologically induced apoptosis [186,187]. There is also evidence that a nonmodified by ERKs mitochondrial HIF-1α form protects cancer cells from apoptosis under hypoxia [188]. ...
Simple Summary
Vitamin D, conventionally considered a nutrient, is a potent hormone regulating many physiological functions. In addition, many studies point to the anticancer activities of calcitriol. However, cancer cells use mechanisms that negate the beneficial effects of calcitriol. Many of these mechanisms control or are controlled by the Hypoxia Inducible transcription Factors (HIFs) that are overexpressed in human cancers due to the development of hypoxia inside the tumors. This review discusses the crosstalk between calcitriol and HIF signaling in order to better understand their relationship to cancer, its prevention, and treatment.
Abstract
Vitamin D is a hormone that, through its action, elicits a broad spectrum of physiological responses ranging from classic to nonclassical actions such as bone morphogenesis and immune function. In parallel, many studies describe the antiproliferative, proapoptotic, antiangiogenic effects of calcitriol (the active hormonal form) that contribute to its anticancer activity. Additionally, epidemiological data signify the inverse correlation between vitamin D levels and cancer risk. On the contrary, tumors possess several adaptive mechanisms that enable them to evade the anticancer effects of calcitriol. Such maladaptive processes are often a characteristic of the cancer microenvironment, which in solid tumors is frequently hypoxic and elicits the overexpression of Hypoxia-Inducible Factors (HIFs). HIF-mediated signaling not only contributes to cancer cell survival and proliferation but also confers resistance to anticancer agents. Taking into consideration that calcitriol intertwines with signaling events elicited by the hypoxic status cells, this review examines their interplay in cellular signaling to give the opportunity to better understand their relationship in cancer development and their prospect for the treatment of cancer.
... In 2016, the Voltage Dependent Anion Channel isoform 3 (VDAC3) was suggested as a putative sensor of mitochondrial ROS levels [11,12]. Hitherto, VDAC1 had been considered a key player in ROS-induced apoptosis [13] as the responsible for the translocation of superoxide anion from mitochondria to cytosol [14]. Located in the outer membrane of eukaryotes mitochondria, VDACs form large aqueous channels that mediate metabolites exchange across the organelle [15,16]. ...
Unraveling the role of VDAC3 within living cells is challenging and still requires a definitive answer. Unlike VDAC1 and VDAC2, the outer mitochondrial membrane porin 3 exhibits unique biophysical features that suggest unknown cellular functions. Electrophysiological studies on VDAC3 carrying selective cysteine mutations and mass spectrometry data about the redox state of such sulfur containing amino acids are consistent with a putative involvement of isoform 3 in mitochondrial ROS homeostasis. Here, we thoroughly examined this issue and provided for the first time direct evidence of the role of VDAC3 in cellular response to oxidative stress. Depletion of isoform 3 but not isoform 1 significantly exacerbated the cytotoxicity of redox cyclers such as menadione and paraquat, and respiratory complex I inhibitors like rotenone, promoting uncontrolled accumulation of mitochondrial free radicals. High-resolution respirometry of transiently transfected HAP1-ΔVDAC3 cells expressing the wild type or the cysteine-null mutant VDAC3 protein, unequivocally confirmed that VDAC3 cysteines are indispensable for protein ability to counteract ROS-induced oxidative stress.
... Truncated VDAC1 was linked to an upregulation of both Oxphos and glycolysis, as well as to resistance to apoptosis (Brahimi-Horn et al., 2012;Brahimi-Horn and Mazure, 2014;Mazure, 2016;Cunha-de Padua et al., 2020). By contrast, knockout of VDAC1 in mouse embryonic fibroblasts (MEF) expressing oncogenic RAS, favors tumor development in mice by promoting metabolic reprogramming (Brahimi-Horn et al., 2015). Beyond hypoxia, under conditions that decrease pyruvate oxidation in the Krebs cycle, mitochondria from tumor cells adapt to oxidize more glutamine as an energy source sustaining tumor growth both through aerobic glycolysis and Oxphos (Mullen et al., 2012). ...
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.
... EGLN2 methylation was associated with hypoxic features while the association of HIF-1α and EGLN2 enabled the identification of patients with poorer OS [197]. Other targets linked to hypoxia such as Cdkn2a (cyclin-dependent kinase inhibitor 2A) or Vdac1 (voltage-dependent anionselective channel 1) [198,199] were identified in an innovative approach aiming to explore novel biomarkers for lung cancer in exhaled breath [200,201]. ...
Lung cancer represents the first cause of death by cancer worldwide and remains a challenging public health issue. Hypoxia, as a relevant biomarker, has raised high expectations for clinical practice. Here, we review clinical and pathological features related to hypoxic lung tumours. Secondly, we expound on the main current techniques to evaluate hypoxic status in NSCLC focusing on positive emission tomography. We present existing alternative experimental approaches such as the examination of circulating markers and highlight the interest in non-invasive markers. Finally, we evaluate the relevance of investigating hypoxia in lung cancer management as a companion biomarker at various lung cancer stages. Hypoxia could support the identification of patients with higher risks of NSCLC. Moreover, the presence of hypoxia in treated tumours could help clinicians predict a worse prognosis for patients with resected NSCLC and may help identify patients who would benefit potentially from adjuvant therapies. Globally, the large quantity of translational data incites experimental and clinical studies to implement the characterisation of hypoxia in clinical NSCLC management.
