Mitochondrial Binding of Hexokinase II Inhibits Bax-induced Cytochrome c Release and Apoptosis

Proapoptotic proteins such as Bax, undergo translocation to the mitochondria during apoptosis, where they mediate the release of intermembrane space proteins including cytochromec. Bax binds to the voltage-dependent anion channel (VDAC). VDAC is a β-barrel protein located in the outer mitochondrial membrane. In planar lipid bilayers, Bax and VDAC form a channel through which cytochrome c can pass. Hexokinase II (HXK II) also binds to VDAC. HXK II catalyzes the first step of glycolysis and is highly expressed in transformed cells, where over 70% of it is bound to the mitochondria. The present study demonstrates that HXK II interferes with the ability of Bax to bind to mitochondria and release cytochrome c. Detachment of HXK II from the mitochondria-enriched fraction isolated from HeLa cells promoted the binding of recombinant Bax-Δ19 and subsequent cytochromec release. Similarly, the addition of recombinant HXK II to the mitochondria-enriched fraction isolated from hepatocytes, cells that do not express HXK II endogenously, prevented the ability of recombinant Bax-Δ19 to bind to the mitochondria and promote cytochrome c release. Similar results were found in intact cells, in which the detachment of mitochondrial bound HXK II or its overexpression potentiated and inhibited, respectively, Bax-induced mitochondrial dysfunction and cell death. Proapoptotic proteins such as Bax, undergo translocation to the mitochondria during apoptosis, where they mediate the release of intermembrane space proteins including cytochromec. Bax binds to the voltage-dependent anion channel (VDAC). VDAC is a β-barrel protein located in the outer mitochondrial membrane. In planar lipid bilayers, Bax and VDAC form a channel through which cytochrome c can pass. Hexokinase II (HXK II) also binds to VDAC. HXK II catalyzes the first step of glycolysis and is highly expressed in transformed cells, where over 70% of it is bound to the mitochondria. The present study demonstrates that HXK II interferes with the ability of Bax to bind to mitochondria and release cytochrome c. Detachment of HXK II from the mitochondria-enriched fraction isolated from HeLa cells promoted the binding of recombinant Bax-Δ19 and subsequent cytochromec release. Similarly, the addition of recombinant HXK II to the mitochondria-enriched fraction isolated from hepatocytes, cells that do not express HXK II endogenously, prevented the ability of recombinant Bax-Δ19 to bind to the mitochondria and promote cytochrome c release. Similar results were found in intact cells, in which the detachment of mitochondrial bound HXK II or its overexpression potentiated and inhibited, respectively, Bax-induced mitochondrial dysfunction and cell death. The major emphasis of apoptosis research was initially focused on the nucleus. This is understandable, given that the nucleus exhibits some of the most striking features of apoptosis, such as chromatin condensation and oligonucleosomal fragmentation of DNA. Recently, however, the involvement of mitochondria in apoptosis has come under close scrutiny. Mitochondria are the power plants of the cell, providing the bulk of ATP production for cellular metabolism. It has been demonstrated that cytochrome c, located in the intermembrane space (IMS) 1IMSintermembrane spaceCTZclotrimazoleHXK IIhexokinase IIG6Pglucose 6-phosphateINDindomethacintHXK IItruncated hexokinase IIVDACvoltage-dependent anion channelHXK2VBDhexokinase II VDAC binding domainPBSCa2+/Mg2+-free phosphate-buffered salineCHAPS3-(3-cholamidopropyl)dimethylammonio-1-propanesulfonic acidANTadenine nucleotide translocator of the mitochondria, is released to the cytosol during apoptosis and helps trigger the activation of caspases, a family of enzymes that is integral to the breakup of apoptotic cells (1Cai J. Yang J. Jones D.P. Biochim. Biophys. Acta. 1998; 1366: 139-149Crossref PubMed Scopus (649) Google Scholar, 2Finucane D.M. Bossy-Wetzel E. Wateruse N.J. Cotter T.G. Green D.R. J. Biol. Chem. 1999; 274: 2225-2233Abstract Full Text Full Text PDF PubMed Scopus (653) Google Scholar, 3Jurgensmeier J.M. Xie Z. Deveraux Q. Ellerby L. Bredesen D. Reed J.C. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 4997-5002Crossref PubMed Scopus (1375) Google Scholar, 4Manon S. Chaudhuri B. Guerin M. FEBS Lett. 1997; 415: 29-32Crossref PubMed Scopus (267) Google Scholar, 5Martinou I. Desagher S. Eskes R. Antonsson B. Andre E. Fakan S. Martinou J.C. J. Cell Biol. 1999; 144: 883-889Crossref PubMed Scopus (264) Google Scholar). Subsequently, a plethora of other proteins that are located in the mitochondrial IMS and are part of the apoptotic machinery have been discovered, including apoptosis-inducing factor, SMAC/DIABLO, caspases 9 and 8, and endonuclease G (6Krajewski S. Krajewska M. Ellerby L.M. Welsh K. Xie Z. Deveraux Q.L. Salvesen G.S. Bredesen D.E. Rosenthal R.E. Fiskum G. Reed J.C. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 5752-5757Crossref PubMed Scopus (483) Google Scholar, 7Lorenzo H.K. Susin S.A. Penninger J. Kroemer G. Cell Death Differ. 1999; 6: 516-524Crossref PubMed Scopus (426) Google Scholar, 8Qin Z.H. Wang Y. Kikly K.K. Sapp E. Kegel K.B. Aronin N. DiFiglia M. J. Biol. Chem. 2001; 276: 8079-8086Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). intermembrane space clotrimazole hexokinase II glucose 6-phosphate indomethacin truncated hexokinase II voltage-dependent anion channel hexokinase II VDAC binding domain Ca2+/Mg2+-free phosphate-buffered saline 3-(3-cholamidopropyl)dimethylammonio-1-propanesulfonic acid adenine nucleotide translocator At present, there is considerable controversy over the mode by which IMS proteins escape from that compartment and enter the cytosol, where they become activated. Disruption of the outer mitochondrial membrane is one obvious mechanism. Due to the greater surface area of the inner mitochondrial membrane compared with the outer mitochondrial membrane, excessive swelling of the mitochondrial matrix results in rupture of the outer mitochondrial membrane and the release of intermembrane space proteins. Indeed, opening of the mitochondrial permeability transition pore with subsequent mitochondrial depolarization and outer mitochondrial membrane rupture does occur in some forms of apoptosis (9Wilson M.R. Cell Death Differ. 1998; 5: 646-652Crossref PubMed Scopus (83) Google Scholar). The permeability transition pore is a large proteinaceous pore that spans both mitochondrial membranes (10Bernardi P. Biochim. Biophys. Acta. 1996; 1275: 5-9Crossref PubMed Scopus (378) Google Scholar). In some instances, inhibition of pore opening prevents many of the typical manifestations of apoptosis and preserves cell viability (11Marchetti P. Hirsch T. Zamzami N. Castedo M. Decaudin D. Susin S.A. Masse B. Kroemer G. J. Immunol. 1996; 157: 4830-4836PubMed Google Scholar, 12Cassarino D.S. Parks J.K. Parker W.D., Jr. Bennett J.P., Jr. Biochim. Biophys. Acta. 1999; 1453: 49-62Crossref PubMed Scopus (271) Google Scholar, 13Bradham C.A. Qian T. Streetz K. Trautwein C. Brenner D.A. Lemasters J.J. Mol. Cell. Biol. 1998; 18: 6353-6364Crossref PubMed Scopus (368) Google Scholar). However, in many cases of apoptosis, mitochondrial depolarization and swelling occur as late events, well after the release of cytochrome c and other IMS proteins has occurred (14Eskes R. Antonsson B. Osen-Sand A. Montessuit S. Richter C. Sadoul R. Mazzei G. Nichols A. Martinou J.C. J. Cell Biol. 1998; 143: 217-224Crossref PubMed Scopus (586) Google Scholar, 15Montessuit S. Mazzei G. Magnenat E. Antonsson B. Protein Expression Purif. 1999; 15: 202-206Crossref PubMed Scopus (39) Google Scholar). In such cases, the release of IMS proteins appears to be more selective and not due to a wholesale disruption of the outer mitochondrial membrane. However, in both instances, the Bcl-2 family of proteins appears to play a key role in the control of outer membrane permeability. The penultimate family member, Bcl-2, was discovered to be overexpressed in a B-cell lymphoma due to a t(11;14)(q23;32) chromosomal translocation (16Akao Y. Seto M. Takahashi T. Kubonishi I. Miyoshi I. Nakazawa S. Tsujimoto Y. Croce C.M. Ueda R. Cancer Res. 1991; 51: 1574-1576PubMed Google Scholar). To date, there are 14 known human homologs of Bcl-2 family proteins that have been localized to the nucleus, endoplasmic reticulum, and mitochondria (17Reed J.C. Miyashita T. S. Wang T. S. C. S. S. M. J. Cell. 1996; PubMed Scopus Google Scholar). At the mitochondria, Bcl-2 proteins can or mitochondrial Bcl-2 and are the of the family that cytochrome c release and The proteins considerable in known as has been demonstrated to through its domain with the voltage-dependent anion channel S. A. T. Tsujimoto Y. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). VDAC is a β-barrel protein that spans the outer mitochondrial membrane M. E. M. 1996; PubMed Scopus Google Scholar, C.A. M. M. J. PubMed Scopus Google Scholar). VDAC ATP and translocation the outer mitochondrial membrane with the adenine nucleotide translocator the inner membrane. Bax has been demonstrated to with VDAC S. M. Tsujimoto Y. 1999; PubMed Scopus Google Scholar). However, in to Bax cytochrome c release and Bax from the cytosol to the mitochondria apoptotic A. J. 1999; 18: PubMed Scopus Google Scholar, J. Cell Biol. 1997; PubMed Scopus Google Scholar). Bax However, demonstrated that Bax forms a channel with VDAC in planar lipid bilayers, which the of cytochromec. over it has been known that cells a of The is known to be due in part to the of hexokinase II (HXK II) in transformed cells A. J. 1997; PubMed Scopus Google Scholar). In HXK II the first step of glucose to glucose In transformed cells, to 70% of the HXK II is bound to the mitochondria through with VDAC M. D. M. J. Biol. PubMed Scopus Google Scholar, M. PubMed Scopus Google Scholar, K.K. J. Biol. Chem. Full Text PDF PubMed Google Scholar). At HXK II to ATP D. Biophys. 1997; PubMed Scopus Google Scholar). The of ATP to HXK II the cells to a greater of glycolysis E. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). This of cellular has been both Bax and HXK II bind to mitochondria through with to the of mitochondrial bound HXK II found in transformed cells on the ability of Bax to In the present that the binding of HXK II to mitochondria prevents recombinant cytochromec release and of In that of mitochondrial bound HXK II the binding of Bax-Δ19 to the mitochondria-enriched fraction and cytochrome c release. recombinant HXK II was found to Bax-Δ19 cytochrome in the mitochondria-enriched fraction isolated from hepatocytes, a cell that does not express HXK In that in intact cells, detachment of mitochondrial bound HXK II results in a of apoptosis by that Bax translocation to the mitochondria and that overexpression of HXK II the of HeLa cells were in with of and under of and cells were for were to the of were as by cells were with of in with II by E. of In cases, the were to a of HeLa cells were in of in of a well a cell of to HeLa cells were with Ca2+/Mg2+-free phosphate-buffered saline after which of was to the Cell viability was by the ability of the cells to of a of was to the and cells were for in a of Cell viability was also the membrane B. J. PubMed Scopus Google Scholar). bound to are with and after the addition of addition from cells that have membrane and HeLa cells were to in as in the to was to a of At the of the was on a and At the of the was to a of which of the cells as by was as a where is the of cells in the a is the after the addition of is the and is the of in The of cell viability results to that of that both of cell viability and are not to apoptosis and to the of hexokinase II were by hexokinase II VDAC binding domain of the was that the to the of of the intact cells T. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). were to cellular were a of in for the of cell viability or for the mitochondria-enriched fraction and HeLa cells were with and in The cells were or for with clotrimazole or of the cells were or with indomethacin for the in the cells in a of were The is on the ability of the to the from the the was and to and The cells were and with Cell were and with was to a of and the was for The were to a and the were in a and cells in were in and with of in or The cells were by for and of or was with of The was by and for of a was to the and or the of was to of the The was by on a in for was by with and I. Desagher S. Eskes R. Antonsson B. Andre E. Fakan S. Martinou J.C. J. Cell Biol. 1999; 144: 883-889Crossref PubMed Scopus (264) Google Scholar). HeLa cells were in and a of the cells were by and for The cell were in and in of and in on for the cells were by of a The was to cells and The mitochondria-enriched fraction membrane was by for The endoplasmic the was from the In mitochondrial was by the control as in and of a with and as The was and through and to of cytochrome c release and Bax binding in intact cells, mitochondria-enriched and were for protein and on by The membranes were and with to cytochrome and to were isolated from hepatocytes, the mitochondria-enriched fraction was isolated the for of the HeLa cell mitochondria-enriched HeLa cells were with a of the the first of the of the of human a a of the was The mitochondria-enriched a of in a of was in a and were as To detachment of the mitochondrial bound HXK the mitochondria-enriched fraction was in that clotrimazole glucose 6-phosphate or a of a to the of hexokinase II a the mitochondria-enriched fraction was or with Bax-Δ19 a of the of cytochrome c the mitochondria-enriched fraction was first for The was and through a and through a and in a to were for protein and on and the were and with to the integral inner membrane protein cytochrome of the fraction was with and on and c was by a to cytochrome c Bax-Δ19 binding was with a to Bax that binds to the a the of was to mitochondria to the outer membrane and release of cytochrome c. express hexokinase the mitochondria-enriched fraction that was isolated from was in to the of recombinant hexokinase II (HXK II) and truncated hexokinase II II) on Bax-Δ19 cytochrome c release. for HeLa cells, the mitochondria-enriched fraction was in a with and as The mitochondria-enriched fraction was with HXK II or II in of HXK II and II were a of of mitochondrial The of HXK II and II is of protein and of the mitochondria were or with a of The mitochondria-enriched fraction was and the mitochondrial and were as with HeLa cell mitochondria for of cytochrome c release and Bax-Δ19 for HXK II and Bax-Δ19 were as of HXK II and a of HXK II binding was the of that of glucose to glucose 6-phosphate in and Bax-Δ19 binding was by of Bax was isolated and as M. A. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus (271) Google Scholar). Bax is was to a human Bax that the for the The was the and of in with The was to the of was to of of and was and was to a of and the were for The cells were with in and The was on and for The was with for The was with and The the bound was with of in with The released Bax was on a a of in with and the was The was in a of The of HXK II was to for and to that for Bax and HXK II the was by to the first in the of HXK The was to the a was to the as The on the mitochondrial a that the of Bax-Δ19 was not due to a of the The mitochondria-enriched fraction was isolated from HeLa cells and found to of mitochondrial bound HXK II has been to release mitochondrial bound HXK II in cells J. R. J. 1998; PubMed Scopus Google Scholar). demonstrated in the addition of of to the mitochondrial fraction isolated from HeLa cells release of HXK II from the mitochondrial fraction to the The of HXK glucose 6-phosphate its from mitochondria J.M. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). of the HeLa cell mitochondria-enriched fraction with of also the release of mitochondrial bound HXK II The of HXK II are and for it to bind to VDAC. a the of HXK II II VDAC binding was to release mitochondrial bound HXK demonstrated in with of in release of HXK II from the HeLa cell mitochondria. to detachment of HXK II from mitochondria with Bax-Δ19 was to the isolated HeLa cell mitochondria-enriched The mitochondrial fraction was and demonstrated in the addition of Bax-Δ19 a of in binding of Bax-Δ19 to the HeLa cell mitochondria-enriched with most of it in the the mitochondria-enriched fraction was with or that release mitochondrial bound HXK binding of Bax-Δ19 to the HeLa cell mitochondria-enriched fraction occurred HXK II from mitochondria on the ability of Bax-Δ19 to release cytochrome the intermembrane that the addition of Bax-Δ19 to a of in release of cytochrome c from the control mitochondria-enriched Bax-Δ19 was to mitochondria-enriched that were with and in and in or cytochrome c release. However, of Bax-Δ19 was to mitochondria-enriched with or there was release of cytochrome c from the mitochondria to the results that detachment of HXK II from mitochondria to a of cytochrome c release with binding of Bax-Δ19 to the mitochondria. a greater of Bax-Δ19 was binding of Bax-Δ19 and cytochrome c release in HeLa cell mitochondria-enriched not express HXK II A. C.A. Cancer Res. 1996; Google Scholar). mitochondria are to the of HXK II on the ability of Bax-Δ19 to bind to the mitochondria-enriched fraction and release cytochrome c. demonstrated in mitochondrial binding become of HXK II of mitochondrial and is by inhibition of binding of Bax-Δ19 in in to the mitochondria-enriched fraction isolated from HeLa cells, the addition of Bax-Δ19 to the mitochondria-enriched fraction in a binding of Bax and the release of cytochrome c. recombinant HXK II of mitochondrial was with the mitochondria-enriched fraction for to by the addition of demonstrated in HXK II prevented the binding of Bax-Δ19 to the mitochondria-enriched fraction and cytochrome c release. the of HXK II are for it to bind to mitochondria. expressed a of HXK II in which the first were truncated with HXK the mitochondria-enriched fraction was with II of mitochondrial to the addition of demonstrated in HXK was to the binding of Bax to the mitochondrial fraction or its of cytochrome c release. of mitochondrial II ability to Bax-Δ19 binding or cytochrome c release not results that HXK II binding to mitochondria is for it to the binding of Bax-Δ19 and the of cytochrome c release. demonstrated a the of HXK II was to HXK II from isolated HeLa cell mitochondria. intact cell a the of HXK II to that demonstrated in of HeLa cells with in the detachment and translocation of HXK II from the mitochondria to the clotrimazole has been demonstrated to the detachment of HXK II from mitochondria in in of HeLa cells with in the translocation of HXK II from the mitochondrial to the ability to mitochondrial bound HXK II in intact cells, the of on Bax-induced cytochrome c release and such as have been demonstrated to apoptosis that is on Bax J. B. PubMed Scopus Google Scholar). a of of cell viability in HeLa cells after of demonstrated in of HeLa cells with indomethacin or clotrimazole However, the were there was a in of the HeLa cells with of the cells by with of HeLa cells with over However, was with there was a of cell with over of the cells by the by indomethacin in with or was on demonstrated in and Bax Bax in HeLa cells and prevented cell in the of or in HeLa cells is on Bax of cells were with a of the first of the of the for The of Bax was as a HeLa cells were for The cells were with the and cell viability was after in a HeLa cells were with a of the first of the of the for The of Bax was as a HeLa cells were for The cells were with the and cell viability was after The of cell viability by the of and or and was due to in and of HeLa cells with and or and a in and a of control of the cells with a of the or with of the prevented the of cell viability by or of apoptotic cell is the of to in or after of of the the cell by in the of that mitochondrial bound HXK II was with binding of Bax to the mitochondria-enriched fraction and cytochrome c release. demonstrated in of HeLa cells with a of Bax binding to the mitochondria-enriched fraction with release of cytochrome c to the in cells for with or and with there was a in the binding of Bax to the mitochondria-enriched fraction 8, and The binding of Bax to the mitochondria by or was by release of cytochrome c from the mitochondria to the cytosol 8, and with or not Bax translocation or cytochrome c release. cells were in cells were with and in with or of the cells with that for apoptotic features II was with of cells apoptotic features II prevents Bax-induced cell Bax HXK cells were with of and of or In cases, the of was to a of At cells were for The of cells was and for features of are the from in a cells were with of and of or In cases, the of was to a of At cells were for The of cells was and for features of are the from The present study demonstrates that mitochondrial bound hexokinase II prevents Bax from with the mitochondria. detachment of HXK II from mitochondria cells to Bax-induced cytochrome c release and to the of are human hexokinase E. Biol. PubMed Google Scholar). and II bind to mitochondria. Hexokinase is found in the D.A. D. 1991; PubMed Scopus Google Scholar). Hexokinase II is expressed in and A. J. 1997; PubMed Scopus Google Scholar). such as HeLa cells express more HXK II or HeLa cells express of protein of HXK II compared with of protein in or HXK II is a protein that is of a and a domain D. Biophys. 1997; PubMed Scopus Google Scholar). This is to have from of a The of HXK II are and for it to bind to VDAC D. Biophys. 1997; PubMed Scopus Google Scholar). However, binding that is by the other of the protein also with VDAC. binding to HXK II to mitochondrial HXK II catalyzes the first and a step in to mitochondrial ATP the mitochondrial bound HXK II can the of glycolysis K.K. J. Biol. Chem. Full Text PDF PubMed Google Scholar, M. Biophys. PubMed Scopus Google Scholar). the by HXK II in transformed cells is on mitochondrial ATP it has been In to where the are ATP and glycolysis a of for This is for transformed cells that and large of for acid and protein In the of are in the to is a for many and in the for E. J. Biol. Chem. Full Text PDF PubMed Google Scholar). VDAC is integral protein that forms a channel in the outer mitochondrial membrane M. E. M. 1996; PubMed Scopus Google Scholar, C.A. J. 1997; PubMed Scopus Google G. I. I. M. Biophys. Res. 1998; PubMed Scopus Google Scholar). The channel a for VDAC to a or are VDAC has been found to be with the the outer and inner mitochondrial membranes D. G. A. M. T. 1998; PubMed Scopus Google Scholar). VDAC and the are of the permeability transition pore found to with VDAC and the is the located in the outer mitochondrial membrane Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). of the promote opening of the permeability transition pore in isolated mitochondria and can apoptosis in intact cells T. Decaudin D. Susin S.A. P. N. M. Kroemer G. Cell Res. 1998; PubMed Scopus Google Scholar, G. K. Jr. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). Bax is a protein that to the mitochondria in some forms of Bax has been demonstrated to with both VDAC and the in in S. M. Tsujimoto Y. 1999; PubMed Scopus Google Scholar, I. Brenner C. Zamzami N. J.M. Susin S.A. Xie Z. S. Reed J.C. Kroemer G. 1998; PubMed Scopus Google Scholar). VDAC and Bax were found to a large pore with greater of VDAC and Bax S. T. T. Tsujimoto Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). c was to through a channel in a planar lipid In to Bax, the VDAC. VDAC to that which HXK II in the present study S. Y. Y. Y. Tsujimoto Y. J. Cell Biol. 2001; PubMed Scopus Google Scholar). prevented Bax-induced cytochrome c release in isolated mitochondria. In of HeLa cells prevented apoptosis by Bax overexpression and potentiated apoptosis by and However, HXK the not binding of Bax to mitochondria. The ability of the to Bax-induced cytochrome c release was to the VDAC to a results that HXK II prevents Bax from binding to mitochondria, the is in with HXK II binds to VDAC and forms a that HXK II the binding of Bax to VDAC through HXK II VDAC to a in which it is to bind expressed in and cell HXK II was found to cell and apoptosis M. T. C. A. Res. 6: Google Scholar, K. N. S. E. N. 2001; 15: PubMed Scopus Google Scholar). The binding of HXK II to mitochondria be in part by B. is highly in many transformed cells Y. M. J. 1999; PubMed Scopus Google Scholar, D.R. S. J.C. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, B. A. M. K. R. 1999; 18: PubMed Scopus Google Scholar). was first as a The has been found to be by a of in mitochondrial bound HXK II was found in cells to undergo apoptosis by or K. N. S. E. N. 2001; 15: PubMed Scopus Google Scholar). was found to the binding of HXK II to mitochondria in cells and to Similar to overexpression of HXK II in cells prevented apoptosis by and also apoptosis in the cell and was with of glycolysis D.R. S. J.C. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, D.R. J.C. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar). HXK II has on the of transformed HXK II is the of the that the by the on which a transformed cell such a However, also that HXK II can apoptosis by binding to the mitochondria and the apoptotic protein Bax from mitochondrial dysfunction and cell death. that promoted HXK II release by on cell viability potentiated the by of the of HXK II found in cells, from the present results it that the binding of HXK II to mitochondria be a for the of