Modulation of the mitochondrial voltage dependent anion channel (VDAC) by curcumin

Tewari, Debanjan; Ahmed, Tofayel; Chirasani, Venkat R.; Singh, Pradeep K.; Maji, Samir K.; Senapati, Sanjib; Bera, Amal Kanti

doi:10.1016/j.bbamem.2014.10.014

Cited by 41 publications

(32 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both modeling and artificial bilayer experiments revealed that the S193E variant opens and closes less frequently than does the wild-type [43] although the open state conductances are similar (3.7 and 3.9 nS, respectively, [44]). In this case, the N-terminal methionine is not present in the native form [45], but presumably remains in the recombinant one.…”

Section: Accepted Manuscriptmentioning

confidence: 93%

The N-terminus of VDAC: Structure, mutational analysis, and a potential role in regulating barrel shape

Shuvo

Ferens

Court

2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

View full text Add to dashboard Cite

A novel feature of the voltage-dependent anion channel (VDAC, mitochondrial porin), is the barrel, comprising an odd number of β-strands and closed by parallel strands. Recent research has focused on the N-terminal segment, which in the available structures, resides in the lumen and is not part of the barrel. In this review, the structural data obtained from vertebrate VDAC are integrated with those from VDAC in artificial bilayers, emphasizing the array of native and tagged versions of VDAC used. The data are discussed with respect to a recent gating model (Zachariae et al. (2012) Structure 20:1-10), in which the N-terminus acts not as a gate on a stable barrel, but rather stabilizes the barrel, preventing its shift into a partially collapsed, low-conductance, closed state. Additionally, the role of the N-terminus in VDAC oligomerization, apoptosis through interactions with hexokinase and its interaction with ATP are discussed briefly.

show abstract

Section: Accepted Manuscriptmentioning

confidence: 93%

The N-terminus of VDAC: Structure, mutational analysis, and a potential role in regulating barrel shape

Shuvo

Ferens

Court

2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

View full text Add to dashboard Cite

show abstract

“…Another drug in trials for cancer, the natural product curcumin, also has been shown to activate AMPK and inhibit mTOR (57)(58)(59). Interestingly, a recent study demonstrated that, similar to itraconazole, curcumin also interferes with VDAC1 function (60).…”

Section: Discussionmentioning

confidence: 99%

Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells

Head

Shi

Zhao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

111

View full text Add to dashboard Cite

Itraconazole, a clinically used antifungal drug, was found to possess potent antiangiogenic and anticancer activity that is unique among the azole antifungals. Previous mechanistic studies have shown that itraconazole inhibits the mechanistic target of rapamycin (mTOR) signaling pathway, which is known to be a critical regulator of endothelial cell function and angiogenesis. However, the molecular target of itraconazole that mediates this activity has remained unknown. Here we identify the major target of itraconazole in endothelial cells as the mitochondrial protein voltage-dependent anion channel 1 (VDAC1), which regulates mitochondrial metabolism by controlling the passage of ions and small metabolites through the outer mitochondrial membrane. VDAC1 knockdown profoundly inhibits mTOR activity and cell proliferation in human umbilical vein cells (HUVEC), uncovering a previously unknown connection between VDAC1 and mTOR. Inhibition of VDAC1 by itraconazole disrupts mitochondrial metabolism, leading to an increase in the cellular AMP:ATP ratio and activation of the AMP-activated protein kinase (AMPK), an upstream regulator of mTOR. VDAC1-knockout cells are resistant to AMPK activation and mTOR inhibition by itraconazole, demonstrating that VDAC1 is the mediator of this activity. In addition, another known VDAC-targeting compound, erastin, also activates AMPK and inhibits mTOR and proliferation in HUVEC. VDAC1 thus represents a novel upstream regulator of mTOR signaling in endothelial cells and a promising target for the development of angiogenesis inhibitors.

show abstract

“…Results of a study by Scharstuhl et al [49] imply that VDAC is involved in fibroblast apoptosis induced by curcumin. Molecular docking followed by mutational analysis indicate that curcumin interacts with amino acid residues in the alpha helical N-terminus of VDAC and in the channel wall, thus restricting the movement of the helix by fixing it in a closed conformation [50]. Therefore, curcumin interferes with opening of the channel, as evidenced by a decrease in VDAC conductance upon treatment with the phenolic compound.…”

Section: Class IV Mitocans: Deregulators Of Vdac/ant Complexmentioning

confidence: 98%

Polyphenols as mitochondria-targeted anticancer drugs

2015

View full text Add to dashboard Cite

Modulation of the mitochondrial voltage dependent anion channel (VDAC) by curcumin

Cited by 41 publications

References 44 publications

The N-terminus of VDAC: Structure, mutational analysis, and a potential role in regulating barrel shape

The N-terminus of VDAC: Structure, mutational analysis, and a potential role in regulating barrel shape

Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells

Polyphenols as mitochondria-targeted anticancer drugs

Contact Info

Product

Resources

About