The voltage-dependent anion channel-1 modulates apoptotic cell death

Zaid, Hilal; Abu-Hamad, Salah; Israelson, Adrian; Nathan, Ilana; Shoshan‐Barmatz, Varda

doi:10.1038/sj.cdd.4401599

Cited by 277 publications

(394 citation statements)

References 48 publications

(112 reference statements)

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“…In this study, the authors suggested that the effect of tBID on OMM permeabilization is through another unidentified OMM protein. The importance of VDAC for OMM permeabilization is further supported by recent evidence that overexpression of VDAC induces apoptosis in various cell types, and this effect is inhibited by BCL-2 and VDAC inhibitors [28,29].…”

Section: The Involvement Of Vdac In Apoptosismentioning

confidence: 76%

Mitochondrial carriers and pores: Key regulators of the mitochondrial apoptotic program?

2007

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Mitochondria play a pivotal role in the process of apoptosis. Alterations in mitochondrial structure and function during apoptosis are regulated by proteins of the BCL-2 family, however their exact mechanism of action is largely unknown. Mitochondrial carriers and pores play an essential role in maintaining the normal function of mitochondria, and BCL-2 family members were shown to interact with several mitochondrial carriers/pores and to affect their function. This review focuses on the involvement of several of these mitochondrial carriers/pores in the regulation of the mitochondrial death pathway.

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Section: The Involvement Of Vdac In Apoptosismentioning

confidence: 76%

Mitochondrial carriers and pores: Key regulators of the mitochondrial apoptotic program?

2007

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“…Despite experimental observations supporting the models depicted in Figures 2 and 3, other investigators have recently suggested that hexokinase-mediated VDAC closure, rather than VDAC opening, may underlie the ability of hexokinases to inhibit apoptosis (Azoulay-Zohar et al, 2004;Zaid et al, 2005). This fundamentally different interpretation was inferred from the ability of HKI to decrease the in vitro conductivity of purified VDAC reconstituted into planar lipid bilayers by approximately 70% and is based upon the assumption that cytochrome c is released via VDAC (AzoulayZohar et al, 2004).…”

Section: Mitochondrial Hexokinases As Downstream Effectors Of Growth mentioning

confidence: 99%

“…Although still incompletely understood, a major landmark in our understanding of the molecular basis of hexokinasemitochondria interaction occurred about 25 years ago when a hexokinase-binding protein isolated from mitochondria (Felgner et al, 1979) was identified as VDAC (Fiek et al, 1982;Linde´n et al, 1982). Subsequent studies have clearly validated the notion that mammalian VDAC directly participates in the specific binding of mitochondrial hexokinases to the OMM (Nakashima et al, 1986;Vyssokikh et al, 2001;Azoulay-Zohar et al, 2004;Zaid et al, 2005). Unlike their mammalian counterparts, yeast hexokinases do not bind mitochondria, and yeast mitochondria do not bind hexokinases (Wilson, 1997b).…”

Section: Mammalian Cells Express Multiple Hexokinase Isoformsmentioning

confidence: 99%

“…In these studies, HKI exhibited a higher affinity for the prototypic VDAC1 isoform than for other mammalian VDAC isoforms and suggested specific involvement of VDAC carboxylterminal extramitochondrial domains in this interaction Aflalo, 1999, 2000). It has also been shown that selective covalent modification (Nakashima et al, 1986;Gelb et al, 1992;Whitesell et al, 2005) or targeted mutation (Zaid et al, 2005) of a specific glutamate residue (E72) selectively inhibits the ability of VDAC to bind hexokinase (Nakashima et al, 1986;De Pinto et al, 1993). VDAC is responsible for regulating the normal exchange of metabolites critical for mitochondrial function across the OMM and into the IMS where they are then accessible to the specific inner mitochondrial membrane (IMM) transport mechanisms responsible for their uptake into the matrix (Colombini, 2004).…”

Section: Mammalian Cells Express Multiple Hexokinase Isoformsmentioning

confidence: 99%

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Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt

2006

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Cell survival has been closely linked to both trophic growth factor signaling and cellular metabolism. Such couplings have obvious physiologic and pathophysiologic implications, but their underlying molecular bases remain incompletely defined. As a common mediator of both the metabolic and anti-apoptotic effects of growth factors, the serine/threonine kinase Akt -also known as protein kinase B or PKB -is capable of regulating and coordinating these inter-related processes. The glucose dependence of the antiapoptotic effects of growth factors and Akt plus a strong correlation between Akt-regulated mitochondrial hexokinase association and apoptotic susceptibility suggest a major role for hexokinases in these effects. Mitochondrial hexokinases catalyse the first obligatory step of glucose metabolism and directly couple extramitochondrial glycolysis to intramitochondrial oxidative phosphorylation, and are thus well suited to play this role. The ability of Akt to regulate energy metabolism appears to have evolutionarily preceded the capacity to control cell survival. This suggests that Akt-dependent metabolic regulatory functions may have given rise to glucose-dependent antiapoptotic effects that evolved as an adaptive sensing system involving hexokinases and serve to ensure mitochondrial homeostasis, thereby coupling metabolism to cell survival. We hypothesize that the enlistment of Akt and hexokinase in the control of mammalian cell apoptosis evolved as a response to the recruitment of mitochondria to the apoptotic cascade. The central importance of mitochondrial hexokinases in cell survival also suggests that they may represent viable therapeutic targets in cancer.

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“…Of note, there are several VDAC isoforms (VDAC1, VDAC2, VDAC3). Although there is no systematic study that has addressed the contribution of VDAC isoforms to apoptosis, it appears that VDAC1 is proapoptotic (Zaid et al, 2005), while VDAC2 might be antiapoptotic, acting as an endogenous inhibitor of Bak (Cheng et al, 2003).…”

Section: Mitochondrial Membrane Permeabilization: the Central Event Omentioning

confidence: 99%

Mitochondria as therapeutic targets for cancer chemotherapy

et al. 2006

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Mitochondria are vital for cellular bioenergetics and play a central role in determining the point-of-no-return of the apoptotic process. As a consequence, mitochondria exert a dual function in carcinogenesis. Cancer-associated changes in cellular metabolism (the Warburg effect) influence mitochondrial function, and the invalidation of apoptosis is linked to an inhibition of mitochondrial outer membrane permeabilization (MOMP). On theoretical grounds, it is tempting to develop specific therapeutic interventions that target the mitochondrial Achilles' heel, rendering cancer cells metabolically unviable or subverting endogenous MOMP inhibitors. A variety of experimental therapeutic agents can directly target mitochondria, causing apoptosis induction. This applies to a heterogeneous collection of chemically unrelated compounds including positively charged a-helical peptides, agents designed to mimic the Bcl-2 homology domain 3 of Bcl-2-like proteins, ampholytic cations, metals and steroid-like compounds. Such MOMP inducers or facilitators can induce apoptosis by themselves (monotherapy) or facilitate apoptosis induction in combination therapies, bypassing chemoresistance against DNA-damaging agents. In addition, it is possible to design molecules that neutralize inhibitor of apoptosis proteins (IAPs) or heat shock protein 70 (HSP70). Such IAP or HSP70 inhibitors can mimic the action of mitochondrion-derived mediators (Smac/DIABLO, that is, second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with a low isoelectric point, in the case of IAPs; AIF, that is apoptosis-inducing factor, in the case of HSP70) and exert potent chemosensitizing effects.

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The voltage-dependent anion channel-1 modulates apoptotic cell death

Cited by 277 publications

References 48 publications

Mitochondrial carriers and pores: Key regulators of the mitochondrial apoptotic program?

Mitochondrial carriers and pores: Key regulators of the mitochondrial apoptotic program?

Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt

Mitochondria as therapeutic targets for cancer chemotherapy

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