Regulation of VDAC trafficking modulates cell death

Abstract

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.

Glucose starvation triggers filamentous septin assemblies in an S. pombe septin-2 deletion mutant

“…The nucleus sometimes shows some decoration as well, but this could be caused simply by ribosomes originating from the continuation of the nuclear membrane into rough endoplasmic reticulum (RER). The mitochondrial outer membrane is not connected with RER and features different properties such as large amounts of voltage gated anion channels (VDAC; Dubey et al, 2016) or associated proteins [e.g. hexokinase (HxKII; Colombini, 1983)] that could be a potential anchor points for the ribosome association observed here.…”

Structure, gating and interactions of the voltage-dependent anion channel

“…Through its interaction with Bax and Bak, VDAC has been suggested to participate in the release of cytochrome c into the cytosol and the activation of the apoptotic cascade (Shimizu et al 2000 ; Tsujimoto and Shimizu 2000 ), while the anti-apoptotic Bcl-x L protein closes the pore by direct binding (Shimizu et al 1999 ). Hexokinase 1 binding to VDAC may suppress apoptosis by modulating VDAC activity and controlling the channel switching between off and on states (Caterino et al 2017 ; Dubey et al 2016 ). VDAC’s inhibition by tubulin could influence ATP trafficking, and even induce a switch, known as the Warburg effect, between oxidative phosphorylation and glycolysis in cancer cells (Maldonado et al 2013 ).…”

VDAC1 as a Player in Mitochondria-Mediated Apoptosis and Target for Modulating Apoptosis

“…Finally, in cancer cells under hypoxic conditions, a fraction of VDAC1 is truncated at the C-terminus (VDAC1-ΔC), and this was shown to confer resistance to cell death [70]. Likewise, it has been shown that VDAC1 over-expression-induced cell death occurs only when the protein is inserted into the mitochondria and proposed that VDAC1 trafficking modulates cell death and that this is regulated by the interaction with HK [71].…”