VDAC Genes Expression and Regulation in Mammals

Abstract

VDACs are pore-forming proteins, coating the mitochondrial outer membrane, and playing the role of main regulators for metabolites exchange between cytosol and mitochondria. In mammals, three isoforms have evolutionary originated, VDAC1, VDAC2, and VDAC3. Despite similarity in sequence and structure, evidence suggests different biological roles in normal and pathological conditions for each isoform. We compared Homo sapiens and Mus musculus VDAC genes and their regulatory elements. RNA-seq transcriptome analysis shows that VDAC isoforms are expressed in human and mouse tissues at different levels with a predominance of VDAC1 and VDAC2 over VDAC3, with the exception of reproductive system. Numerous transcript variants for each isoform suggest specific context-dependent regulatory mechanisms. Analysis of VDAC core promoters has highlighted that, both in a human and a mouse, VDAC genes show features of TATA-less ones. The level of CG methylation of the human VDAC genes revealed that VDAC1 promoter is less methylated than other two isoforms. We found that expression of VDAC genes is mainly regulated by transcription factors involved in controlling cell growth, proliferation and differentiation, apoptosis, and bioenergetic metabolism. A non-canonical initiation site termed “the TCT/TOP motif,” the target for translation regulation by the mTOR pathway, was identified in human VDAC2 and VDAC3 and in every murine VDACs promoter. In addition, specific TFBSs have been identified in each VDAC promoter, supporting the hypothesis that there is a partial functional divergence. These data corroborate our experimental results and reinforce the idea that gene regulation could be the key to understanding the evolutionary specialization of VDAC isoforms.

Voltage Dependent Anion Channel 3 (VDAC3) protects mitochondria from oxidative stress

“…As proposed by Zinghirino et al [ 59 ], this discrepancy could be related to the minor stability of VDAC3 transcripts. Alternatively, cells would maintain the activity of VDAC3 promoter constitutively high in order to promptly increase protein expression upon specific stimuli [ 59 ]. However, the mechanism by which VDAC3 is up-regulated following oxidative insults needs to be elucidated: in the light of above, we speculate that this mechanism may include both an increase of mRNA stability and the modulation of gene expression, through the use of a polypyrimidine stretch localized within VDAC3 promoter and identified as a target of oxidative and metabolic stress [ 60 ].…”

“…Consistent with these observations, the parental cell line drastically overexpressed VDAC3 in response to prolonged exposure to rotenone, menadione and paraquat, stressing the importance of this specific VDAC isoform in fighting oxidative stress. To this regard, it should be outlined that, under physiological conditions, VDAC3 transcript is the less abundant isoform, despite its promoter retains the greater transcriptional activity compared to those of VDAC1 and VDAC2 [ 59 ]. As proposed by Zinghirino et al [ 59 ], this discrepancy could be related to the minor stability of VDAC3 transcripts.…”

“…To this regard, it should be outlined that, under physiological conditions, VDAC3 transcript is the less abundant isoform, despite its promoter retains the greater transcriptional activity compared to those of VDAC1 and VDAC2 [ 59 ]. As proposed by Zinghirino et al [ 59 ], this discrepancy could be related to the minor stability of VDAC3 transcripts. Alternatively, cells would maintain the activity of VDAC3 promoter constitutively high in order to promptly increase protein expression upon specific stimuli [ 59 ].…”

The lncRNA BDNF-AS/WDR5/FBXW7 axis mediates ferroptosis in gastric cancer peritoneal metastasis by regulating VDAC3 ubiquitination

“…Our further studies confirmed that VDAC3 expression was upregulated in GC tissues and GC PM tissues. Previous studies indicated that VDAC3 could affect cell ferroptosis by regulating the mitochondrial entry and exit of iron ions 19 , 20 , 45 . Excessive iron accumulation could result in ROS production through the Fenton reaction and then cause ferroptosis 46 , 47 .…”

Strategies for Successful Over-Expression of Human Membrane Transport Systems Using Bacterial Hosts: Future Perspectives

“…In humans, three isoforms have been described: VDAC1, VDAC2, and VDAC3. Despite the similarity in sequence and structure, evidence suggests different biological roles in normal and pathological conditions for each isoform [ 215 ]. Either wild-type VDAC1 or VDAC2 have been expressed as C-terminal 6His-tagged proteins in the E. coli M15(pREP4) strain in standard conditions ( Table 3 ), purified by nickel-chelating chromatography, and reconstituted in planar bilayer membranes in a functional form [ 133 ].…”