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

Maurya, Svetlana Rajkumar; Mahalakshmi, Radhakrishnan

doi:10.1074/jbc.m113.493692

Cited by 40 publications

(94 citation statements)

References 39 publications

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“…Lipid compositions may not only affect the structural plasticity of VDACs required for gating, but also their general stability. For example, low protein-to-lipid ratios enhance the stability of human VDAC1 against thermal and chemical denaturation (Maurya and Mahalakshmi, 2013). Furthermore, a similar effect on stability was observed for human VDAC2 when being incorporated into LDAO micelles (Maurya and Mahalakshmi, 2014).…”

Section: Ion Conductance By Vdacsmentioning

confidence: 67%

Voltage-dependent anion channels: the wizard of the mitochondrial outer membrane

Mertins

Psakis

Essen

2014

Biological Chemistry

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Voltage dependent anion channels (VDACs) are the most abundant proteins in the outer mitochondrial membrane. Although they are essential in metabolite exchange, cell defense and apoptosis, the molecular mechanism of these VDAC-mediated processes remains elusive. Here we review recent progress in terms of VDACs' structure and regulation, with a special focus on the molecular aspects of gating and the interaction with effector proteins.

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Section: Ion Conductance By Vdacsmentioning

confidence: 67%

Voltage-dependent anion channels: the wizard of the mitochondrial outer membrane

Mertins

Psakis

Essen

2014

Biological Chemistry

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“…The three isoforms share several structural and functional similarities yet significant differences exist between them in terms of functionality [22,[27][28][29]. Recombinant VDAC1 and VDAC2 demonstrated channel activity upon reconstitution into a lipid bilayer (PLB) [30].…”

Section: Vdacmentioning

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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“…VDAC2 gene knockout is lethal (74), whereas knockout of isoforms 1 and 3 are not, suggesting important functional differences for the isoforms. VDAC2 is an abundant brain isoform (75) and is the most cysteine-rich isoform (11 cysteines in mouse, 9 cysteines in human), with most of them predicted to be located on exposed loops on the intermembrane space side of the channel and all of them in the reduced state and available for modification (76). In order to identify specific succinated target cysteines we first prepared in vitro succinated VDAC from mitochondrial tissue fractions from the brain, using these we confirmed Cys 77 and Cys 104 as target sites of succination for VDAC 2 (supplemental Fig.…”

Section: Protein Succination In Leigh Syndromementioning

confidence: 99%

“…Interestingly this unique change in VDAC2 is predicted to decrease the pI from 7.44 to 6.81. This may have important implications for altering the protein:protein interactions in a given region, in addition to the predicted VDAC cysteine:lipid membrane interactions (76).…”

Section: Protein Succination In Leigh Syndromementioning

confidence: 99%

Succination is Increased on Select Proteins in the Brainstem of the NADH dehydrogenase (ubiquinone) Fe-S protein 4 (Ndufs4) Knockout Mouse, a Model of Leigh Syndrome

Piroli

Manuel

Clapper

et al. 2016

Molecular & Cellular Proteomics

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Elevated fumarate concentrations as a result of Krebs cycle inhibition lead to increases in protein succination, an irreversible post-translational modification that occurs when fumarate reacts with cysteine residues to generate S-(2-succino)cysteine (2SC). Metabolic events that reduce NADH re-oxidation can block Krebs cycle activity; therefore we hypothesized that oxidative phosphorylation deficiencies, such as those observed in some mitochondrial diseases, would also lead to increased protein succination. Using the Ndufs4 knockout (Ndufs4 KO) mouse, a model of Leigh syndrome, we demonstrate for the first time that protein succination is increased in the brainstem (BS), particularly in the vestibular nucleus. Importantly, the brainstem is the most affected region exhibiting neurodegeneration and astrocyte and microglial proliferation, and these mice typically die of respiratory failure attributed to vestibular nucleus pathology. In contrast, no increases in protein succination were observed in the skeletal muscle, corresponding with the lack of muscle pathology observed in this model. 2D SDS-PAGE followed by immunoblotting for succinated proteins and MS/MS analysis of BS proteins allowed us to identify the voltagedependent anion channels 1 and 2 as specific targets of succination in the Ndufs4 knockout. Using targeted mass spectrometry, Cys 77 and Cys 48 were identified as endogenous sites of succination in voltage-dependent anion channels 2. Given the important role of voltage-dependent anion channels isoforms in the exchange of ADP/ATP between the cytosol and the mitochondria, and the already decreased capacity for ATP synthesis in the Ndufs4 KO mice, we propose that the increased protein succination observed in the BS of these animals would further decrease the already compromised mitochondrial function. These data suggest that fumarate is a novel bio- We previously identified the formation of S-(2-succino)cysteine (2SC) 1 (protein succination) as a result of the irreversible reaction of fumarate with reactive cysteine thiols (1, 2). Fumarate concentrations are increased during adipogenesis and adipocyte maturation (2,3), and the excess of glucose and insulin leads to augmented protein succination in the adipose tissue of type 2 diabetic mice (4, 5). Protein succination is also specifically increased in fumarate hydratase deficient hereditary leiomyomatosis and renal cell carcinoma (HLRCC), because of the decreased conversion of fumarate to malate (6, 7). In both cases, intracellular fumarate concentrations are elevated; in fumarate hydratase deficient cells, the fumarate concentration is about 5 mM (8) Author contributions: G.G.P. and N.F. designed research; G.G.P., A.M.M., A.C.C., M.D.W., J.E.B., A.Q., and N.F. performed research; J.E.B., R.D.P., and A.Q. contributed new reagents or analytic tools; G.G.P., A.M.M., M.D.W., J.E.B., and N.F. analyzed data; G.G.P. and N.F. wrote the paper. 1 The abbreviations used are: 2SC, S-(2-succino)cysteine; 2D, twodimensional; BS, brainstem; CB, cerebellum; C PE , cystei...

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

Cited by 40 publications

References 39 publications

Voltage-dependent anion channels: the wizard of the mitochondrial outer membrane

Voltage-dependent anion channels: the wizard of the mitochondrial outer membrane

The mitochondrial voltage-dependent anion channel 1 in tumor cells

Succination is Increased on Select Proteins in the Brainstem of the NADH dehydrogenase (ubiquinone) Fe-S protein 4 (Ndufs4) Knockout Mouse, a Model of Leigh Syndrome

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