Mitochondrial VDAC and hexokinase together modulate plant programmed cell death

Godbole, Ashwini; Dubey, Anil Kumar; Reddy, P. Srinivasa; Udayakumar, M.; Mathew, M. K.

doi:10.1007/s00709-012-0470-y

Cited by 41 publications

(40 citation statements)

References 59 publications

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“…18 Much of the data underlying this conclusion came from the overexpression of one or other of the proteins. Here we studied the effect of reducing HxKII levels in the presence of endogenous VDAC levels.…”

Section: Resultsmentioning

confidence: 99%

“…16–18 Previous studies from our 18 as well as other 2,10 laboratories have shown that elevation in the expression of both VDAC and HxK is associated with increased growth rate as seen in cancerous cells exhibiting the Warburg Effect, 9 whereas increased expression of any one of the proteins tilts the balance of cell survival and death. 10,18 Increased expression of HxK alone makes cells resistant to cell death. 19,20 This protective effect of overexpression of HxK is limited in the absence of VDAC as shown in VDAC-silenced human dopaminergic SH-SY5Y neuroblastoma cells.…”

Section: Introductionmentioning

confidence: 97%

“…18,21,22 The mechanism of amelioration remains to be elucidated. Zaid et al have shown that, in planar bilayer membranes, HxK and RuR interact with VDAC directly, leading to decreases in VDAC conductance.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of VDAC trafficking modulates cell death

Dubey

Godbole

Mathew

2016

Cell Death Discovery

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The voltage-dependent anion channel (VDAC) and mitochondria-associated hexokinase (HxK) have crucial roles in both cell survival and death. Both the individual abundances and their ratio seem to influence the balance of survival and death and are thus critical in scenarios, such as neurodegeneration and cancer. Elevated levels of both VDAC and HxK have been reported in cancerous cells. Physical interaction is surmised and specific residues or regions involved have been identified, but details of the interaction and the mechanism by which it modulates survival are yet to be elucidated. We and others have shown that heterologous expression of VDAC can induce cell death, which can be mitigated by concomitant overexpression of HxK. We have also observed that upon overexpression, fluorescently tagged VDAC is distributed between the cytosol and mitochondria. In this study, we show that cell death ensues only when the protein, which is synthesized on cytoplasmic ribosomes, migrates to the mitochondrion. Further, coexpression of rat HxK II (rHxKII) can delay the translocation of human VDAC1 (hVDAC1) protein to mitochondria and thereby inhibit VDAC-induced cell death. Variation in the level of HxK protein as seen endogenously in different cell lines, or as experimentally manipulated by silencing and overexpression, can lead to differential VDAC translocation kinetics and related cell death. The N-terminal region of HxK and the Glu73 residue of hVDAC1, which have previously been implicated in a physical interaction, are required for cytosolic retention of VDAC. Finally, we show that, in otherwise unperturbed cells in culture, there is a small but significant amount of soluble VDAC in the cytosol present in a complex with HxK. This complex could well determine how a cell is poised with respect to incoming thanatopic signals, thereby tilting the survival/death balance in pharmacologically interesting situations, such as neurodegeneration and cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Regulation of VDAC trafficking modulates cell death

Dubey

Godbole

Mathew

2016

Cell Death Discovery

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“…This process induces the permeabilization of the mitochondrial OM (e.g., as a mitochondrial transition pore), which is indeed the point of no return in the intrinsic apoptotic pathway. As a proteinaceous docking platform of the outer mitochondrial membrane, VDACs interact directly with a plethora of pro-and anti-apoptotic factors, which are either members of the Bcl-2 protein family such as Bcl-xL (Malia and Wagner, 2007;Arbel et al, 2012), Bid/tBid (Rostovtseva et al, 2004), Bax/Bak (Shimizu et al, 2001) and hexokinases (Godbole et al, 2013) or Bnip3 (Chaanine et al, 2013). The precise molecular functions and stoichiometries of these VDAC/apoptotic factor complexes are poorly understood, although tentative structural predictions for several VDAC/effector complexes have been suggested (Veresov and Davidovskii, 2014).…”

Section: Non-transport Functions Of Vdacsmentioning

confidence: 99%

Voltage-dependent anion channels: the wizard of the mitochondrial outer membrane

Mertins

Psakis

Essen

2014

Biological Chemistry

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Voltage dependent anion channels (VDACs) are the most abundant proteins in the outer mitochondrial membrane. Although they are essential in metabolite exchange, cell defense and apoptosis, the molecular mechanism of these VDAC-mediated processes remains elusive. Here we review recent progress in terms of VDACs' structure and regulation, with a special focus on the molecular aspects of gating and the interaction with effector proteins.

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“…Recently, Cheng et al (2011) identified that OsHXK1, 7, and 8 in O. sativa are located in the cytoplasm and nucleus, since they lack the plastidic transit peptide and the membrane anchor domain; thus, these enzymes are classified as type-C HXKs [10]. The variety and multiple subcellular localizations of HXKs indicate that these proteins may have functions in various physiological processes of plants, such as anther dehiscence, pollen germination [11], stomatal closure [12], germination [13], programmed cell death [14], and responses to abiotic or biotic stresses [15]. It has been identified that HXKs have important roles in sugar metabolism and sugar signaling [7,16].…”

Section: Introductionmentioning

confidence: 99%

Structure, Expression, and Functional Analysis of the Hexokinase Gene Family in Cassava

Geng

Yao

Wang

et al. 2017

IJMS

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Hexokinase (HXK) proteins play important roles in catalyzing hexose phosphorylation and sugar sensing and signaling. To investigate the roles of HXKs in cassava tuber root development, seven HXK genes (MeHXK1–7) were isolated and analyzed. A phylogenetic analysis revealed that the MeHXK family can be divided into five subfamilies of plant HXKs. MeHXKs were clearly divided into type A (MeHXK1) and type B (MeHXK2–7) based on their N-terminal sequences. MeHXK1–5 all had typical conserved regions and similar protein structures to the HXKs of other plants; while MeHXK6–7 lacked some of the conserved regions. An expression analysis of the MeHXK genes in cassava organs or tissues demonstrated that MeHXK2 is the dominant HXK in all the examined tissues (leaves, stems, fruits, tuber phloems, and tuber xylems). Notably, the expression of MeHXK2 and the enzymatic activity of HXK were higher at the initial and expanding tuber stages, and lower at the mature tuber stage. Furthermore, the HXK activity of MeHXK2 was identified by functional complementation of the HXK-deficient yeast strain YSH7.4-3C (hxk1, hxk2, glk1). The gene expression and enzymatic activity of MeHXK2 suggest that it might be the main enzyme for hexose phosphorylation during cassava tuber root development, which is involved in sucrose metabolism to regulate the accumulation of starch.

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Mitochondrial VDAC and hexokinase together modulate plant programmed cell death

Cited by 41 publications

References 59 publications

Regulation of VDAC trafficking modulates cell death

Regulation of VDAC trafficking modulates cell death

Voltage-dependent anion channels: the wizard of the mitochondrial outer membrane

Structure, Expression, and Functional Analysis of the Hexokinase Gene Family in Cassava

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