On a fully closed state of native human type-1 VDAC enriched in Nonidet P40

Thinnes, Friedrich P.; Burckhardt, Gerhard

doi:10.1016/j.ymgme.2012.08.015

Cited by 8 publications

(3 citation statements)

References 9 publications

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“…Conversely, the increased binding of HK to the mitochondria of cancer cells may play a role in mediating increased synthesis and uptake of cholesterol into the mitochondria of cancer cells [93]. Recently, it has been proposed that a glycine motif (GxxxG) in the N-terminal part of VDAC1, localized between positions 20-24, is responsible for cholesterol binding [94].…”

Section: Vdac1 In Cholesterol and Lipid Transportmentioning

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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Section: Vdac1 In Cholesterol and Lipid Transportmentioning

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

View full text Add to dashboard Cite

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“…( 81 ). Recently, it has been suggested that a glycine rich motif 21 GYGFG 25 sequence in the N-terminal part of VDAC1 is responsible for cholesterol binding ( 82 ). Cholesterol at high levels can reduce the activity of membrane-associated proteins and, thus, inhibit the metabolic functions of VDAC1 ( 83 ).…”

Section: Vdac1 As a Multi-substrate Transportermentioning

confidence: 99%

Voltage-Dependent Anion Channel 1 As an Emerging Drug Target for Novel Anti-Cancer Therapeutics

et al. 2017

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Cancer cells share several properties, high proliferation potential, reprogramed metabolism, and resistance to apoptotic cues. Acquiring these hallmarks involves changes in key oncogenes and non-oncogenes essential for cancer cell survival and prosperity, and is accompanied by the increased energy requirements of proliferating cells. Mitochondria occupy a central position in cell life and death with mitochondrial bioenergetics, biosynthesis, and signaling are critical for tumorigenesis. Voltage-dependent anion channel 1 (VDAC1) is situated in the outer mitochondrial membrane (OMM) and serving as a mitochondrial gatekeeper. VDAC1 allowing the transfer of metabolites, fatty acid ions, Ca2+, reactive oxygen species, and cholesterol across the OMM and is a key player in mitochondrial-mediate apoptosis. Moreover, VDAC1 serves as a hub protein, interacting with diverse sets of proteins from the cytosol, endoplasmic reticulum, and mitochondria that together regulate metabolic and signaling pathways. The observation that VDAC1 is over-expressed in many cancers suggests that the protein may play a pivotal role in cancer cell survival. However, VDAC1 is also important in mitochondria-mediated apoptosis, mediating release of apoptotic proteins and interacting with anti-apoptotic proteins, such as B-cell lymphoma 2 (Bcl-2), Bcl-xL, and hexokinase (HK), which are also highly expressed in many cancers. Strategically located in a “bottleneck” position, controlling metabolic homeostasis and apoptosis, VDAC1 thus represents an emerging target for anti-cancer drugs. This review presents an overview on the multi-functional mitochondrial protein VDAC1 performing several functions and interacting with distinct sets of partners to regulate both cell life and death, and highlights the importance of the protein for cancer cell survival. We address recent results related to the mechanisms of VDAC1-mediated apoptosis and the potential of associated proteins to modulate of VDAC1 activity, with the aim of developing VDAC1-based approaches. The first strategy involves modification of cell metabolism using VDAC1-specific small interfering RNA leading to inhibition of cancer cell and tumor growth and reversed oncogenic properties. The second strategy involves activation of cancer cell death using VDAC1-based peptides that prevent cell death induction by anti-apoptotic proteins. Finally, we discuss the potential therapeutic benefits of treatments and drugs leading to enhanced VDAC1 expression or targeting VDAC1 to induce apoptosis.

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“…The study of Li et al (Best et al, 2007 ), furthermore, puts type-1 VDAC another time in touch with the extrinsic apoptotic pathway. Together, the results help to functionally understand much evidence indicating that plasmalemmal VDAC-1 forms the channel part of a volume regulated anion channel complex (VRAC, ORDIC, VSOR, Icl swell ) that, in terms of molecular identity, still awaits definition (Dermietzel et al, 1994 ; Thinnes and Reymann, 1997 ; Thinnes et al, 2000 ; Okada et al, 2004 ; Elinder et al, 2005 ; Thinnes and Burckhardt, 2012 ; Thinnes, 2013 ; Akita and Okada, 2014 ).…”

Section: Discussionmentioning

confidence: 89%

After all, plasmalemmal expression of type-1 VDAC can be understood. Phosphorylation, nitrosylation, and channel modulators work together in vertebrate cell volume regulation and either apoptotic pathway

On a fully closed state of native human type-1 VDAC enriched in Nonidet P40

Cited by 8 publications

References 9 publications

The mitochondrial voltage-dependent anion channel 1 in tumor cells

The mitochondrial voltage-dependent anion channel 1 in tumor cells

Voltage-Dependent Anion Channel 1 As an Emerging Drug Target for Novel Anti-Cancer Therapeutics

After all, plasmalemmal expression of type-1 VDAC can be understood. Phosphorylation, nitrosylation, and channel modulators work together in vertebrate cell volume regulation and either apoptotic pathway

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