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VDAC2-specific cellular functions and the underlying structure.

ABSTRACT: 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 Ca(2+) 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.

SUBMITTER: Naghdi S

PROVIDER: S-EPMC5092071 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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VDAC2-specific cellular functions and the underlying structure.

Naghdi Shamim S Hajnóczky György G

Biochimica et biophysica acta 20160423 10

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 Ca(2+) transport at least in cardiomyocytes, which is unlikely to be explained simply by the expression level of VDAC2. Furthermore, a strictly isofor ...[more]

PMID: 27116927

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Project description:Cellular senescence is a program of irreversible cell cycle arrest that normal cells undergo in response to progressive shortening of telomeres, changes in telomeric structure, oncogene activation or oxidative stress. The underlying signalling pathways, potentially of major clinicopathological relevance, are unknown. A major stumbling block to studying senescence has been the absence of suitable model systems because of the asynchrony of this process in heterogeneous cell populations. To simplify this process many investigators study oncogene-induced senescence due to expression of activated oncogenes where senescence occurs prematurely without telomere attrition and can be induced acutely in a variety of cell types. We have taken a different approach by making use of the finding that reconstitution of telomerase activity by introduction of the catalytic subunit of human telomerase alone is incapable of immortalising all human somatic cells, but inactivation of the p16-pRB and p53-p21 pathways are required in addition. The ability of SV40 large T antigen to inactivate the p16-pRB and p53-p21 pathways has enabled us to use a thermolabile mutant of LT antigen, in conjunction with hTERT, to develop conditionally immortalised human (HMF3A) fibroblasts that are immortal but undergo an irreversible growth arrest when the thermolabile LT antigen is inactivated leading to activation of pRB and p53. When these cells cease dividing, senescence-associated- b-galactosidase activity is induced and the growth-arrested cells have morphological features and express genes in common with senescent cells. Since these cells growth arrest in a synchronous manner they are an excellent starting point for dissecting the pathways that underlie cellular senescence and act downstream of p16-pRB and p53-p21 pathways. We have combined genome-wide expression profiling with genetic complementation to undertake identification of genes that are differentially expressed when these conditionally immortalised human fibroblasts undergo senescence upon activation of the p16-pRB and p53-p21 tumour suppressor pathways. Genes differentially expressed upon senescence will be identified by comparing arrays from growing versus senescent cells. Changes in gene expression due to the temperature shift will be eliminated by comparing with array data from the non-conditional HMF3S cells grown at 34°C ±0.5°C and 38°C ±0.5°C. To determine if the changes in gene expression upon senescence are specific and reversible, the set of differential genes will then be overlaid with array data from cells in which senescence has been bypassed by inactivation of the p16-pRB and p53-p21 tumour suppressor pathways

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VDAC2-specific cellular functions and the underlying structure.

Publications

VDAC2-specific cellular functions and the underlying structure.

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