Activated Mitofusin 2 Signals Mitochondrial Fusion, Interferes with Bax Activation, and Reduces Susceptibility to Radical Induced Depolarization

Mitochondrial fusion in higher eukaryotes requires at least two essential GTPases, Mitofusin 1 and Mitofusin 2 (Mfn2). We have created an activated mutant of Mfn2, which shows increased rates of nucleotide exchange and decreased rates of hydrolysis relative to wild type Mfn2. Mitochondrial fusion is stimulated dramatically within heterokaryons expressing this mutant, demonstrating that hydrolysis is not requisite for the fusion event, and supporting a role for Mfn2 as a signaling GTPase. Although steady-state mitochondrial fusion required the conserved intermembrane space tryptophan residue, this requirement was overcome within the context of the hydrolysis-deficient mutant. Furthermore, the punctate localization of Mfn2 is lost in the dominant active mutants, indicating that these sites are functionally controlled by changes in the nucleotide state of Mfn2. Upon staurosporine-stimulated cell death, activated Bax is recruited to the Mfn2-containing puncta; however, Bax activation and cytochrome c release are inhibited in the presence of the dominant active mutants of Mfn2. The dominant active form of Mfn2 also protected the mitochondria against free radical-induced permeability transition. In contrast to staurosporine-induced outer membrane permeability transition, pore opening induced through the introduction of free radicals was dependent upon the conserved intermembrane space residue. This is the first evidence that Mfn2 is a signaling GTPase regulating mitochondrial fusion and that the nucleotide-dependent activation of Mfn2 concomitantly protects the organelle from permeability transition. The data provide new insights into the critical relationship between mitochondrial membrane dynamics and programmed cell death. Mitochondrial fusion in higher eukaryotes requires at least two essential GTPases, Mitofusin 1 and Mitofusin 2 (Mfn2). We have created an activated mutant of Mfn2, which shows increased rates of nucleotide exchange and decreased rates of hydrolysis relative to wild type Mfn2. Mitochondrial fusion is stimulated dramatically within heterokaryons expressing this mutant, demonstrating that hydrolysis is not requisite for the fusion event, and supporting a role for Mfn2 as a signaling GTPase. Although steady-state mitochondrial fusion required the conserved intermembrane space tryptophan residue, this requirement was overcome within the context of the hydrolysis-deficient mutant. Furthermore, the punctate localization of Mfn2 is lost in the dominant active mutants, indicating that these sites are functionally controlled by changes in the nucleotide state of Mfn2. Upon staurosporine-stimulated cell death, activated Bax is recruited to the Mfn2-containing puncta; however, Bax activation and cytochrome c release are inhibited in the presence of the dominant active mutants of Mfn2. The dominant active form of Mfn2 also protected the mitochondria against free radical-induced permeability transition. In contrast to staurosporine-induced outer membrane permeability transition, pore opening induced through the introduction of free radicals was dependent upon the conserved intermembrane space residue. This is the first evidence that Mfn2 is a signaling GTPase regulating mitochondrial fusion and that the nucleotide-dependent activation of Mfn2 concomitantly protects the organelle from permeability transition. The data provide new insights into the critical relationship between mitochondrial membrane dynamics and programmed cell death. The mitochondria sit at the crossroad of hundreds of chemical reactions that are essential for the life and death of a cell. The dynamic behavior of these organelles has only just begun to be examined, and the implications of steady-state fission, fusion, motility, and cristae remodeling events in the control of the mitochondrial activity are not yet known. Studies in different model organisms are addressing this question by investigating the molecular mechanisms that govern mitochondrial dynamics to gain insights into the physiological triggers and consequences of these events. Mitochondrial fusion in mammalian cells requires at least two essential outer membrane GTPases, Mitofusin 1 (Mfn1) 1The abbreviations used are: Mfn1 and Mfn2, Mitofusin 1 and Mitofusin 2, respectively; CFP, cyan fluorescent protein; ΔΨ, mitochondrial electrochemical potential; DRP1, dynamin-related protein 1; ECFP, enhanced cyan fluorescent protein; fmk, fluoromethyl ketone; FP, fluorescent protein; Fzo1p, Fuzzy Onion 1 protein; GFP, green fluorescent protein; GST, glutathione S-transferase; His, hexahistidine; HR, heptad repeat; IMS, intermembrane space; Mant 6GMP-PNP, N-methylanthraniloyl guanosine 5′-(β,γ-imino)triphosphate; PBS, phosphate-buffered saline; PEG, polyethylene glycol; STS, staurosporine; YFP, yellow fluorescent protein; Z, benzylxoycarbonyl. 1The abbreviations used are: Mfn1 and Mfn2, Mitofusin 1 and Mitofusin 2, respectively; CFP, cyan fluorescent protein; ΔΨ, mitochondrial electrochemical potential; DRP1, dynamin-related protein 1; ECFP, enhanced cyan fluorescent protein; fmk, fluoromethyl ketone; FP, fluorescent protein; Fzo1p, Fuzzy Onion 1 protein; GFP, green fluorescent protein; GST, glutathione S-transferase; His, hexahistidine; HR, heptad repeat; IMS, intermembrane space; Mant 6GMP-PNP, N-methylanthraniloyl guanosine 5′-(β,γ-imino)triphosphate; PBS, phosphate-buffered saline; PEG, polyethylene glycol; STS, staurosporine; YFP, yellow fluorescent protein; Z, benzylxoycarbonyl. and Mitofusin 2 (Mfn2) (1Santel A. Fuller M.T. J. Cell Sci. 2001; 114: 867-874Crossref PubMed Google Scholar, 2Rojo M. Legros F. Chateau D. Lombes A. J. Cell Sci. 2002; 115: 1663-1674Crossref PubMed Google Scholar, 3Santel A. Frank S. Gaume B. Herrler M. Youle R.J. Fuller M.T. J. Cell Sci. 2003; 116: 2763-2774Crossref PubMed Scopus (306) Google Scholar, 4Legros F. Lombes A. Frachon P. Rojo M. Mol. Biol. Cell. 2002; 13: 4343-4354Crossref PubMed Scopus (498) Google Scholar, 5Eura Y. Ishihara N. Yokota S. Mihara K. J. Biochem. (Tokyo). 2003; 134: 333-344Crossref PubMed Scopus (308) Google Scholar, 6Chen H. Detmer S.A. Ewald A.J. Griffin E.E. Fraser S.E. Chan D.C. J. Cell Biol. 2003; 160: 189-200Crossref PubMed Scopus (1763) Google Scholar). These proteins span the outer membrane twice, and in addition to their amino-terminal GTPase domain, they have two conserved hydrophobic heptad repeats, HR1 and HR2, which are exposed to the cytosol (2Rojo M. Legros F. Chateau D. Lombes A. J. Cell Sci. 2002; 115: 1663-1674Crossref PubMed Google Scholar, 7Koshiba T. Detmer S.A. Kaiser J.T. Chen H. McCaffery Chan D.C. PubMed Scopus Google Scholar). The of Mfn1 has to mitochondrial and the of the that form a that in to mitochondria T. Detmer S.A. Kaiser J.T. Chen H. McCaffery Chan D.C. PubMed Scopus Google Scholar). of is their intermembrane space which a conserved tryptophan residue. In this of the protein is required for mitochondrial fusion and has to to sites of membrane between the and outer membrane S. D. B. J. Cell Biol. 2001; PubMed Scopus Google Scholar). Although Mfn1 and Mfn2 are evidence in mitochondrial and in of Mfn1 cells has that Mfn1 to a role in mitochondrial T. Detmer S.A. Kaiser J.T. Chen H. McCaffery Chan D.C. PubMed Scopus Google Scholar, N. Y. Mihara K. J. Cell Sci. PubMed Scopus Google and that in the intermembrane space GTPase dominant S. B. Sci. S. A. PubMed Scopus Google Scholar). The role of Mfn2 in mitochondrial fusion has is required for fusion and be in have that the nucleotide and hydrolysis of the two proteins are N. Y. Mihara K. J. Cell Sci. PubMed Scopus Google the that the two different the fusion Y. Ishihara N. Yokota S. Mihara K. J. Biochem. (Tokyo). 2003; 134: 333-344Crossref PubMed Scopus (308) Google Scholar). These the that mitochondrial motility, of a fusion pore to and to mitochondrial membrane the of these molecular the proteins not and in have a of proteins required for mitochondrial fusion, the outer membrane H. J. Cell Biol. 2001; PubMed Scopus Google Scholar, A. J. J. Cell Biol. 2003; 160: PubMed Scopus Google Scholar, H. J. Biol. PubMed Scopus Google the membrane H. Biochem. 2003; PubMed Scopus Google Scholar, S. M. 2003; PubMed Scopus Google Scholar, M. F. J. Biol. 2003; PubMed Scopus Google an protein S. N. B. Mol. Biol. Cell. 2003; PubMed Scopus Google and S. F. M. N. B. Mol. Biol. Cell. 2002; 13: PubMed Scopus Google Scholar). of the in the of mitochondrial dynamics the physiological of mitochondrial and fusion steady-state of Mfn1 Mfn2 are H. Detmer S.A. Ewald A.J. Griffin E.E. Fraser S.E. Chan D.C. J. Cell Biol. 2003; 160: 189-200Crossref PubMed Scopus (1763) Google demonstrating an essential role of mitochondrial fusion for In within the Mfn2 have in from type and of of these within the conserved GTPase K. H. K. A. T. M. Y. T. Y. K. 116: PubMed Scopus Google Scholar, S. M. N. J. M. A. J. Y. Y. S. A. PubMed Scopus Google Scholar). evidence that Mfn2 signaling activity has from that the Mfn2 as an which the and signaling from at the membrane D. Y. D. P. S. J. Cell Biol. PubMed Scopus Google Scholar). Although the for this is these that Mfn2 the state of the mitochondria is into signaling of the mitochondrial is into signaling events is the evidence for a role of mitochondrial dynamics in the of two of the proteins required for mitochondrial fission, and DRP1, are also essential for programmed cell death Y. Mol. Cell. Biol. 2003; PubMed Scopus Google Scholar, Y. J. Biol. 2003; PubMed Scopus Google Scholar, D. K. M.T. J. Cell Sci. PubMed Scopus Google Scholar, M. Youle R.J. Mol. Biol. Cell. PubMed Scopus Google Scholar). by and activation of Bax at the of mitochondria a death indicating an essential role for this membrane protein in M. Youle R.J. Mol. Biol. Cell. PubMed Scopus Google Scholar). of not dramatically Bax cytochrome c release is and mitochondrial is in these cells M. Youle R.J. Mol. Biol. Cell. PubMed Scopus Google Scholar, M. J. Cell Biol. 2003; 160: PubMed Scopus Google Scholar). In of a protein required for mitochondrial fusion, in which are to the of electrochemical and cytochrome c release M. Youle R.J. Mol. Biol. Cell. PubMed Scopus Google Scholar, A. N. A. P. J. Biol. 2003; PubMed Scopus Google Scholar). In of the two proteins against different S. Y. J. Biol. PubMed Scopus Google Scholar). These data the of mitochondrial in the of mitochondrial dynamics and the mitochondrial to programmed cell death. the evidence that Mfn1 a role in mitochondrial Y. Ishihara N. Yokota S. Mihara K. J. Biochem. (Tokyo). 2003; 134: 333-344Crossref PubMed Scopus (308) Google Scholar, N. Y. Mihara K. J. Cell Sci. PubMed Scopus Google have the of Mfn2 in the of mitochondrial fusion and the GTPase activity of Mfn2 to the of programmed cell death. and Mfn2 was by Mfn2 was for into and and was as the and a of to The was into the for The and for protein from cell also and used in this was as the and a of to the tryptophan at a The was into the for was by the of by and and this the into the the the wild type GTPase of the The was from for and and into the H. Biol. PubMed Google Scholar). was from Mfn2 was against a and a Mfn2 to of was a against fluorescent proteins used for from was to steady-state in c from and from cell signaling and from used for was from and was from and of and as in H. Biol. PubMed Google electrochemical cells at for cell for and cells by at the The presence of protein was by at the of for and for cell. 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Cell. 2002; 13: 4343-4354Crossref PubMed Scopus (498) Google Scholar). that the of the to that the of mitochondria not between the cells the a at and the through a The was through an two and to the and and as The protein was the the and not The as and in for of a of nucleotide hydrolysis of Mfn2 was essential for mitochondrial fusion, a mutant. in the mutant was to nucleotide and exchange of Mfn2 and yet the of nucleotide the within the from the activated M. Biochem. PubMed Scopus Google Scholar, A.J. H. A. M. K. PubMed Scopus Google Scholar, N. M. J. 2001; PubMed Scopus Google by for is A. 2001; PubMed Scopus Google We first the nucleotide exchange of this wild type Mfn2 and by from cells fusion cells wild type as a is the of the and is to fusion H. K. B. M. Cell. PubMed Scopus Google Scholar). of the are by their rates of hydrolysis and nucleotide which in nucleotide that proteins for their the evidence that Mfn2 rates of nucleotide hydrolysis and N. Y. Mihara K. J. Cell Sci. 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PubMed Scopus Google Scholar). data that within the of Mfn2 nucleotide exchange relative to the wild type the rates to the rates for the We the rates of hydrolysis the the release of the from the protein from cells M. K. M. PubMed Scopus Google Scholar). of of which is the rates for of protein of of Although of this be the of of nucleotide nucleotide this to be the rates of exchange for wild type Mfn2 are and The rates of hydrolysis have for are to rates of 2 M. K. M. PubMed Scopus Google Scholar, M. J. Biol. PubMed Scopus Google demonstrating the of the Although the mutant Mfn2 increased rates of nucleotide of hydrolysis relative to the wild type protein Although the of of GTPases, exchange proteins in the Mfn2 from cell data that in Mfn2 the nucleotide and hydrolysis of the Mfn2 in Mitochondrial in a the consequences of the GTPase mutant by cells wild type GTPase mutant a mutant the GTPase of cells the wild type Mfn2 in increased the mitochondrial which upon of as a (1Santel A. Fuller M.T. J. Cell Sci. 2001; 114: 867-874Crossref PubMed Google Scholar, 2Rojo M. Legros F. Chateau D. Lombes A. J. Cell Sci. 2002; 115: 1663-1674Crossref PubMed Google Scholar, 4Legros F. Lombes A. Frachon P. Rojo M. Mol. Biol. Cell. 2002; 13: 4343-4354Crossref PubMed Scopus (498) Google Scholar). M. Gaume B. Frank S. A. A. Fuller M. Youle R.J. J. Cell Biol. 2002; PubMed Scopus Google was in the mitochondrial of the GTPase mutant in the of which to be at the of was the of these In of the mutant in mitochondria into that in a 2 and data not to in the Mfn1 GTPase mutant T. Detmer S.A. Kaiser J.T. Chen H. McCaffery Chan D.C. PubMed Scopus Google Scholar). These are to Mfn2 of mitochondrial outer membrane D. K. M.T. J. Cell Sci. PubMed Scopus Google not mitochondrial In these not by the presence of the of not We that the of the Mfn2 upon the conserved Mfn2 only the two of which is a conserved tryptophan that a This is within the in indicating that this not the of Mfn2. in however, the of the mitochondria is and the organelles of a mutant the and are also in a of Mfn2 indicating that the punctate localization not upon the conserved is by the nucleotide state that the and not at sites of mitochondrial fusion, they the and they not at sites of not that the mitochondria within cells Mfn2 and mutants their electrochemical the within cells a and the in a as in In the was between 1 and in of the cells of in of the cells fluorescent of 1 of the not in a cells higher of Mfn2, of cells fluorescent These data that electrochemical is a in cells of into mitochondria of of of of A. of in a new Cell a the fusion of mitochondria in cells expressing these a that fusion between cells different proteins F. Lombes A. Frachon P. Rojo M. Mol. Biol. Cell. 2002; 13: 4343-4354Crossref PubMed Scopus (498) Google Scholar, 5Eura Y. Ishihara N. Yokota S. Mihara K. J. Biochem. (Tokyo). 2003; 134: 333-344Crossref PubMed Scopus (308) Google Scholar, 6Chen H. Detmer S.A. Ewald A.J. Griffin E.E. Fraser S.E. Chan D.C. J. Cell Biol. 2003; 160: 189-200Crossref PubMed Scopus (1763) Google Scholar). from heterokaryons proteins within F. Lombes A. Frachon P. Rojo M. Mol. Biol. Cell. 2002; 13: 4343-4354Crossref PubMed Scopus (498) Google Scholar, 5Eura Y. Ishihara N. Yokota S. Mihara K. J. Biochem. (Tokyo). 2003; 134: 333-344Crossref PubMed Scopus (308) Google Scholar, 6Chen H. Detmer S.A. Ewald A.J. Griffin E.E. Fraser S.E. Chan D.C. J. Cell Biol. 2003; 160: 189-200Crossref PubMed Scopus (1763) Google Scholar). from cells expressing also mitochondria within a however, of the heterokaryons expressing within 2 fusion between mitochondria expressing organelles within the addition of in of the cell of the fusion shows that the the mitochondria are within the This fusion between mitochondria was the of mitochondria from cell into is a in mammalian In control mitochondria within the the cell in the In the of the mitochondria the mitochondria fusion of mitochondria to within This that the presence of within of mitochondria a of events that to mitochondrial the to be the first dominant mutant that mitochondrial The inhibited the fusion, the requirement for the GTPase In addition to a role in have the requirement for the of for mitochondrial fusion S. D. B. J. Cell Biol. 2001; PubMed Scopus Google Scholar). fusion was inhibited between mitochondria and the of mitochondrial fusion by the was by the within the mutant indicating that the conserved is not required for the fusion event, a role in the activation of Mfn2. by that the mitochondria not into a they are through The in cells to the wild type indicating that the of the mitochondrial is the fusion that of the fusion are different of cells not between the of the mitochondria in the cells to the of the outer membrane This be by the of S. D. B. J. Cell Biol. 2001; PubMed Scopus Google to membrane in cells expressing of and membrane that the of the mitochondrial that the Mfn2 protein is within the demonstrating that these are at least in from the outer mitochondrial membrane of this in membrane the cristae and their to electrochemical and mitochondrial fusion within cells expressing within a the of the T. Detmer S.A. Kaiser J.T. Chen H. McCaffery Chan D.C. PubMed Scopus Google Scholar). was membrane between the mitochondria demonstrating that the not of mitochondrial Mfn2 Bax c and the of dynamic changes in mitochondrial the of the of Mfn2 activation the mitochondrial to two different of of programmed death by in the and activation of Bax to the as by an that the active form of Bax S. A. A. S. S. K. B. J. Cell Biol. PubMed Scopus Google Scholar). T. A.J. 2001; PubMed Scopus Google Scholar, M. D. B. S. J. Cell Biol. 2001; PubMed Scopus Google the of Bax activation the of cytochrome c release by and a cells Y. Mol. Biol. Cell. 2001; PubMed Scopus Google Scholar, J. Cell Biol. PubMed Scopus Google Scholar, Mol. Biol. Cell. 2001; PubMed Scopus Google which has to mitochondrial and cytochrome c release from mitochondria M. J. Cell Biol. 2003; 160: PubMed Scopus Google Scholar, S. Gaume B. F. Youle R.J. Cell. 2001; PubMed Scopus Google Scholar). only of these cells cytochrome c release of of cells Bax activation of this of Bax activation increased a release of cytochrome c not as has within cells M. Gaume B. Frank S. A. A. Fuller M. Youle R.J. J. 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Y. Mihara K. J. Cell Sci. PubMed Scopus Google Scholar). have the nucleotide and hydrolysis of a mutant form of Mfn2, and that this mutant has hydrolysis and increased nucleotide exchange the wild type protein This mutant to the consequences of a dominant active form of Mfn2. mutants have a of the hydrolysis-deficient mutant of Mfn2 in a of mitochondrial fusion, and the of the mitochondrial a of new the of the mitochondrial Furthermore, have that the conserved tryptophan within the intermembrane space of Mfn2 is not essential to form a fusion pore is required to fusion within the context of the wild type GTPase. The also to that the punctate localization of Mfn2 M. Gaume B. Frank S. A. A. Fuller M. Youle R.J. J. Cell Biol. 2002; PubMed Scopus Google is by the nucleotide The hydrolysis-deficient mutants of Mfn2 that mitochondrial fusion not form the mutants that mitochondrial fusion are in these the activated Mfn2 Bax cytochrome c and free radical-induced permeability transition. these data a role for Mfn2 as a of mitochondrial fusion and as a nucleotide-dependent of the The fusion that Mfn2 is a in the activated is of signaling to mitochondria to in an is within the mitochondrial outer membrane of the mitochondria in that events in the and fusion of mitochondria the are a of molecular events that to this in fusion, increased as as the activation of the fusion data that Mfn2 a as a of the through the of and as a GTPase of events. These events the activation of which has to in mitochondrial and fusion T. Detmer S.A. Kaiser J.T. Chen H. McCaffery Chan D.C. PubMed Scopus Google Scholar, N. Y. Mihara K. J. Cell Sci. PubMed Scopus Google Scholar, S. B. Sci. S. A. PubMed Scopus Google Scholar). supporting a role for Mfn2 as a signaling GTPase has from demonstrating that cells Mfn2 a of events H. Detmer S.A. Ewald A.J. Griffin E.E. Fraser S.E. Chan D.C. J. Cell Biol. 2003; 160: 189-200Crossref PubMed Scopus (1763) Google a role for Mfn2 in regulating mitochondrial data are also the role for Mfn2 as a of the signaling D. Y. D. P. S. J. Cell Biol. PubMed Scopus Google Scholar). that signaling at the the of Mfn2 to a signaling provide a for to of events at a are the physiological triggers that in fusion that this is required for the of nucleotide exchange in Mfn2. In this the GTPase within the protein in the state within the fusion not be as in 2 and the tryptophan is critical in against free radical-induced permeability that mitochondrial Mfn2 through this to mitochondrial fusion in to free and of Mitochondrial fusion and by and between and physiological this between mitochondrial fusion and permeability pore a to against that to cell death. cells Mfn2 a in membrane H. Detmer S.A. Ewald A.J. Griffin E.E. Fraser S.E. Chan D.C. J. Cell Biol. 2003; 160: 189-200Crossref PubMed Scopus (1763) Google and to Mfn2 in a in membrane and D. S. N. B. J. J. M. H. M. M. H. F. M. A. J. Biol. 2003; PubMed Scopus Google Scholar). In addition to against free radical-induced permeability transition, the data that activated Mfn2 Bax activation and cytochrome c This a of the mitochondrial fusion as a of the that the activation of Mfn2 concomitantly permeability and mitochondrial fusion, the data that these two are has that mitochondrial fusion events are inhibited an M. D. Chen H. Chan D.C. Youle R.J. J. Cell Biol. PubMed Scopus Google data indicating that Mfn2 be in the form to for activation of Although the by which Mfn2 Bax activation is is that the punctate Mfn2 sites for activated Bax and outer membrane permeability transition, and upon activation of Mfn2, critical within these the activation of Mfn2 for fusion the that the two events cytochrome c release and requisite for M. Youle R.J. Cell 2003; PubMed Scopus Google Scholar, A. S.A. Cell Biol. 2003; PubMed Scopus Google of activated Mfn2 of the Bax activation and cytochrome c be and they in mitochondrial and an Y. Mol. Cell. Biol. 2003; PubMed Scopus Google Scholar, Y. J. Biol. 2003; PubMed Scopus Google Scholar, M. Youle R.J. Mol. Biol. Cell. PubMed Scopus Google Scholar, M. J. Cell Biol. 2003; 160: PubMed Scopus Google Scholar, S. Gaume B. F. Youle R.J. Cell. 2001; PubMed Scopus Google Scholar). be to the and to the molecular events that the GTPase of Mfn2 mitochondrial fusion and the control of permeability transition. We are to the have an essential role in the of this We are to for the of and for and to of for the used in this We of the and for critical the

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