VDAC3 as a sensor of oxidative state of the intermembrane space of mitochondria: the putative role of cysteine residue modifications

Reina, Simona; Checchetto, Vanessa; Saletti, Rosaria; Gupta, Ankit; Chaturvedi, Deepti; Guardiani, Carlo; Guarino, Francesca; Scorciapino, Mariano Andrea; Magrì, Andrea; Foti, Salvatore; Ceccarelli, Matteo; Messina, Angela; Mahalakshmi, Radhakrishnan; Szabó, Ildikò; Pinto, Vito De

doi:10.18632/oncotarget.6850

Cited by 78 publications

(131 citation statements)

References 53 publications

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“…Expression, Purification and Refolding of His 6 -tagged VDAC Isoforms-The preparation of refolded VDAC isoforms was performed essentially as described (90). In brief, Escherichia coli BL21(DE3) cells were transformed with plasmid pET21a containing the VDAC isoform-coding sequences.…”

Section: Methodsmentioning

confidence: 99%

Novel Compounds Targeting the Mitochondrial Protein VDAC1 Inhibit Apoptosis and Protect against Mitochondrial Dysfunction

Ben-Hail

Begas-Shvartz

Shalev

et al. 2016

Journal of Biological Chemistry

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102

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Edited by Linda SpremulliApoptosis is thought to play a critical role in several pathological processes, such as neurodegenerative diseases (i.e. Parkinson's and Alzheimer's diseases) and various cardiovascular diseases. Despite the fact that apoptotic mechanisms are well defined, there is still no substantial therapeutic strategy to stop or even slow this process. Thus, there is an unmet need for therapeutic agents that are able to block or slow apoptosis in neurodegenerative and cardiovascular diseases. The outer mitochondrial membrane protein voltage-dependent anion channel 1 (VDAC1) is a convergence point for a variety of cell survival and death signals, including apoptosis. Recently, we demonstrated that VDAC1 oligomerization is involved in mitochondrion-mediated apoptosis. Thus, VDAC1 oligomerization represents a prime target for agents designed to modulate apoptosis. Here, high-throughput compound screening and medicinal chemistry were employed to develop compounds that directly interact with VDAC1 and prevent VDAC1 oligomerization, concomitant with an inhibition of apoptosis as induced by various means and in various cell lines. The compounds protected against apoptosis-associated mitochondrial dysfunction, restoring dissipated mitochondrial membrane potential, and thus cell energy and metabolism, decreasing reactive oxidative species production, and preventing detachment of hexokinase bound to mitochondria and disruption of intracellular Ca 2؉ levels. Thus, this study describes novel drug candidates with a defined mechanism of action that involves inhibition of VDAC1 oligomerization, apoptosis, and mitochondrial dysfunction. The compounds VBIT-3 and VBIT-4 offer a therapeutic strategy for treating different diseases associated with enhanced apoptosis and point to VDAC1 as a promising target for therapeutic intervention.Mitochondria play crucial roles in cellular energy generation and metabolism, maintenance of the cell redox potential, calcium homeostasis, pH control and fatty acid oxidation, cell signaling, proliferation, differentiation, aging, and death (1). It is therefore not surprising that mitochondrial dysfunction is associated with various human diseases (1, 2).Located at the outer mitochondrial membrane (OMM), 2 the voltage-dependent anion channel (VDAC) serves as a mitochondrial gatekeeper. Three VDAC isoforms have been discovered (3), but only for VDAC1 is there a complete set of structural and functional information available. VDAC1 controls the metabolic and energy cross-talk between mitochondria and the rest of the cell, mediating the fluxes of ions, nucleotides, and other metabolites across the OMM (4 -7).

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Section: Methodsmentioning

confidence: 99%

Novel Compounds Targeting the Mitochondrial Protein VDAC1 Inhibit Apoptosis and Protect against Mitochondrial Dysfunction

Ben-Hail

Begas-Shvartz

Shalev

et al. 2016

Journal of Biological Chemistry

Self Cite

102

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“…They might play a role in redox regulation, protein–protein interactions or might have an effect on the stability of β-barrels and on VDAC2 interaction with the lipid environment [46–48]. In line with these findings, C′s in VDAC3 have shown to be in different oxidation states and were implicated in the stability of the channel and in controlling reactive oxygen species (ROS) levels close to the OMM [49,50]. …”

Section: Structurementioning

confidence: 98%

VDAC2-specific cellular functions and the underlying structure

Naghdi

Hajnóczky

2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Voltage Dependent Anion-selective Channel 2 (VDAC2) contributes to oxidative metabolism by sharing a role in solute transport across the outer mitochondrial membrane (OMM) with other isoforms of the VDAC family, VDAC1 and VDAC3. Recent studies revealed that VDAC2 also has a distinctive role in mediating sarcoplasmic reticulum to mitochondria local Ca2+ transport at least in cardiomyocytes, which is unlikely to be explained simply by the expression level of VDAC2. Furthermore, a strictly isoform-dependent VDAC2 function was revealed in the mitochondrial import and OMM-permeabilizing function of pro-apoptotic Bcl-2 family proteins, primarily Bak in many cell types. In addition, emerging evidence indicates a variety of other isoform-specific engagements for VDAC2. Since VDAC isoforms display 75% sequence similarity, the distinctive structure underlying VDAC2-specific functions is an intriguing problem. In this paper we summarize studies of VDAC2 structure and functions, which suggest a fundamental and exclusive role for VDAC2 in health and disease. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.

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“…It has been shown recently that all mammalian VDAC isoforms are able to form channels of comparable characteristic (31, 46, 47). Therefore, it may be speculated that dynamic movement of N-terminal helix defined as the vital element of the voltage-dependence and resulting conductance control [e.g., De Pinto et al (48)] is impaired in all VDAC isoforms due to the protein modification or interaction with mHtt.…”

Section: Discussionmentioning

confidence: 99%

The Association of VDAC with Cell Viability of PC12 Model of Huntington’s Disease

et al. 2016

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It is becoming increasingly apparent that mitochondria dysfunction plays an important role in the pathogenesis of Huntington’s disease (HD), but the underlying mechanism is still elusive. Thus, there is a still need for further studies concerning the upstream events in the mitochondria dysfunction that could contribute to cell death observed in HD. Taking into account the fundamental role of the voltage-dependent anion-selective channel (VDAC) in mitochondria functioning, it is reasonable to consider the channel as a crucial element in HD etiology. Therefore, we applied inducible PC12 cell model of HD to determine the relationship between the effect of expression of wild type and mutant huntingtin (Htt and mHtt, respectively) on cell survival and mitochondria functioning in intact cells under conditions of undergoing cell divisions. Because after 48 h of Htt and mHtt expression differences in mitochondria functioning co-occurred with differences in the cell viability, we decided to estimate the effect of Htt and mHtt expression lasted for 48 h on VDAC functioning. Therefore, we isolated VDAC from the cells and tested the preparations by black lipid membrane system. We observed that the expression of mHtt, but not Htt, resulted in changes of the open state conductance and voltage-dependence when compared to control cells cultured in the absence of the expression. Importantly, for all the VDAC preparations, we observed a dominant quantitative content of VDAC1, and the quantitative relationships between VDAC isoforms were not changed by Htt and mHtt expression. Thus, Htt and mHtt-mediated functional changes of VDAC, being predominantly VDAC1, which occur shortly after these protein appearances in cells, may result in differences concerning mitochondria functioning and viability of cells expressing Htt and mHtt. The assumption is important for better understanding of cytotoxicity as well as cytoprotection mechanisms of potential clinical application.

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VDAC3 as a sensor of oxidative state of the intermembrane space of mitochondria: the putative role of cysteine residue modifications

Cited by 78 publications

References 53 publications

Novel Compounds Targeting the Mitochondrial Protein VDAC1 Inhibit Apoptosis and Protect against Mitochondrial Dysfunction

Novel Compounds Targeting the Mitochondrial Protein VDAC1 Inhibit Apoptosis and Protect against Mitochondrial Dysfunction

VDAC2-specific cellular functions and the underlying structure

The Association of VDAC with Cell Viability of PC12 Model of Huntington’s Disease

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