Mitofusin 2 Protects Cerebellar Granule Neurons against Injury-induced Cell Death

Of the GTPases involved in the regulation of the fusion machinery, mitofusin 2 (Mfn2) plays an important role in the nervous system as point mutations of this isoform are associated with Charcot Marie Tooth neuropathy. Here, we investigate whether Mfn2 plays a role in the regulation of neuronal injury. We first examine mitochondrial dynamics following different modes of injury in cerebellar granule neurons. We demonstrate that neurons exposed to DNA damage or oxidative stress exhibit extensive mitochondrial fission, an early event preceding neuronal loss. The extent of mitochondrial fragmentation and remodeling is variable and depends on the mode and the severity of the death stimuli. Interestingly, whereas mitofusin 2 loss of function significantly induces cell death in the absence of any cell death stimuli, expression of mitofusin 2 prevents cell death following DNA damage, oxidative stress, and K+ deprivation induced apoptosis. More importantly, whereas wild-type Mfn2 and the hydrolysis-deficient mutant of Mfn2 (Mfn2RasG12V) function equally to promote fusion and lengthening of mitochondria, the activated Mfn2RasG12V mutant shows a significant increase in the protection of neurons against cell death and release of proapoptotic factor cytochrome c. These findings highlight a signaling role for Mfn2 in the regulation of apoptosis that extends beyond its role in mitochondrial fusion. Of the GTPases involved in the regulation of the fusion machinery, mitofusin 2 (Mfn2) plays an important role in the nervous system as point mutations of this isoform are associated with Charcot Marie Tooth neuropathy. Here, we investigate whether Mfn2 plays a role in the regulation of neuronal injury. We first examine mitochondrial dynamics following different modes of injury in cerebellar granule neurons. We demonstrate that neurons exposed to DNA damage or oxidative stress exhibit extensive mitochondrial fission, an early event preceding neuronal loss. The extent of mitochondrial fragmentation and remodeling is variable and depends on the mode and the severity of the death stimuli. Interestingly, whereas mitofusin 2 loss of function significantly induces cell death in the absence of any cell death stimuli, expression of mitofusin 2 prevents cell death following DNA damage, oxidative stress, and K+ deprivation induced apoptosis. More importantly, whereas wild-type Mfn2 and the hydrolysis-deficient mutant of Mfn2 (Mfn2RasG12V) function equally to promote fusion and lengthening of mitochondria, the activated Mfn2RasG12V mutant shows a significant increase in the protection of neurons against cell death and release of proapoptotic factor cytochrome c. These findings highlight a signaling role for Mfn2 in the regulation of apoptosis that extends beyond its role in mitochondrial fusion. It has been recently demonstrated that the apoptotic program includes the regulated induction of mitochondrial fragmentation (1Frank S. Gaume B. Bergmann-Leitner E.S. Leitner W.W. Robert E.G. Catez F. Smith C.L. Youle R.J. Dev. Cell. 2001; 1: 515-525Abstract Full Text Full Text PDF PubMed Scopus (1400) Google Scholar, 2Lee Y.J. Jeong S.Y. Karbowski M. Smith C.L. Youle R.J. Mol. Biol. Cell. 2004; 15: 5001-5011Crossref PubMed Scopus (824) Google Scholar). In addition, it has been shown that the rate of mitochondrial fusion is reduced early in the apoptotic program (3Delivani P. Adrain C. Taylor R.C. Duriez P.J. Martin S.J. Mol. Cell. 2006; 21: 761-773Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, 4Karbowski M. Arnoult D. Chen H. Chan D.C. Smith C.L. Youle R.J. J. Cell Biol. 2004; 164: 493-499Crossref PubMed Scopus (342) Google Scholar), which together with the activation of the fission machinery leads to a morphological shift of the mitochondria to the fragmented state. The regulatory mechanisms and functional importance of these events during death remain unclear. For example, it is not clear whether the inhibition of mitochondrial fusion is an essential step in apoptosis or if fragmentation is promoted mainly because of the increase in fission. In addition, it has been shown that the loss of either Drp1 or hFis1 delayed, but did not block cell death, questioning the importance of the mitochondria morphological shift in the apoptotic cascade (5Estaquier J. Arnoult D. Cell Death Differ. 2007; 14: 1086-1094Crossref PubMed Scopus (237) Google Scholar, 6Parone P.A. James D.I. Da Cruz S. Mattenberger Y. Donze O. Barja F. Martinou J.C. Mol. Cell Biol. 2006; 26: 7397-7408Crossref PubMed Scopus (198) Google Scholar). In this context, there is an emerging emphasis on the examination of mitochondrial fusion in the context of cell death. Mitochondrial fusion is regulated by at least three essential GTPases, the outer membrane-anchored proteins mitofusin 1 (Mfn1), 3The abbreviations used are: Mfn, mitofusin; CGN, cerebellar granule neurons; MOI, multiplicity of infection; ROS, reactive oxygen species; PBS, phosphate-buffered saline; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; GFP, green fluorescent protein; OCT, ornithine carbamyl transferase; YFP, yellow fluorescent protein; DIV, days in vitro. 3The abbreviations used are: Mfn, mitofusin; CGN, cerebellar granule neurons; MOI, multiplicity of infection; ROS, reactive oxygen species; PBS, phosphate-buffered saline; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; GFP, green fluorescent protein; OCT, ornithine carbamyl transferase; YFP, yellow fluorescent protein; DIV, days in vitro. and mitofusin 2 (Mfn2) along with the intermembrane space GTPase, Opa1 (7Shaw J.M. Nunnari J. Trends Cell Biol. 2002; 12: 178-184Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar, 8Chen 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 (1706) Google Scholar). Although the functions of Mfn2 overlap with Mfn1 in the process of mitochondrial fusion (9Detmer S.A. Chan D.C. J. Cell Biol. 2007; 176: 405-414Crossref PubMed Scopus (219) Google Scholar), there are clear distinctions between these two GTPases. Perhaps most informative of their distinct function is their biochemical difference in nucleotide binding and hydrolysis properties, where Mfn1 has a faster GTPase hydrolysis rate and higher affinity for nucleotide relative to Mfn2 (10Ishihara N. Eura Y. Mihara K. J. Cell Sci. 2004; 117: 6535-6546Crossref PubMed Scopus (492) Google Scholar, 11Eura Y. Ishihara N. Yokota S. Mihara K. J. Biochem. (Tokyo). 2003; 134: 333-344Crossref PubMed Scopus (300) Google Scholar). In addition, Mfn1, but not Mfn2, has been shown to genetically interact with Opa1 (12Cipolat S. Martins de Brito O. Dal Zilio B. Scorrano L. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 15927-15932Crossref PubMed Scopus (870) Google Scholar), a member of the dynamin family of mechanoenzymes. This relationship with Opa1 would suggest that Mfn1 plays a central role with Opa1 in the fusion process. In an in vitro mitochondrial docking assay, expression of Mfn1 significantly enhanced the tethering reaction, whereas Mfn2 resulted in tethering with low efficiency, suggesting a secondary role for Mfn2 in docking (10Ishihara N. Eura Y. Mihara K. J. Cell Sci. 2004; 117: 6535-6546Crossref PubMed Scopus (492) Google Scholar). Recently, compelling evidence has emerged supporting additional roles for Mfn2 that goes beyond the regulation of the mitochondrial fusion. First, Mfn2 is colocalized in punctate with Bax and Drp1 at sites of future fission (13Karbowski M. Lee Y.J. Gaume B. Jeong S.Y. Frank S. Nechushtan A. Santel A. Fuller M. Smith C.L. Youle R.J. J. Cell Biol. 2002; 159: 931-938Crossref PubMed Scopus (658) Google Scholar). This suggests that Mfn2 activity may affect mitochondrial recruitment of Bax or Drp1 during cell death. Second, Mfn2, but not Mfn1, can interact directly with Ced9 or Bclxl in HEK293 cells, suggesting a mechanism for cross-talk with antiapoptotic Bcl family proteins (3Delivani P. Adrain C. Taylor R.C. Duriez P.J. Martin S.J. Mol. Cell. 2006; 21: 761-773Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar). Third, Mfn2, not Mfn1, has been shown to modulate metabolism through function of complex 1, IV, and V (14Bach D. Pich S. Soriano F.X. Vega N. Baumgartner B. Oriola J. Daugaard J.R. Lloberas J. Camps M. Zierath J.R. Rabasa-Lhoret R. Wallberg-Henriksson H. Laville M. Palacin M. Vidal H. Rivera F. Brand M. Zorzano A. J. Biol. Chem. 2003; 278: 17190-17197Abstract Full Text Full Text PDF PubMed Scopus (637) Google Scholar, 15Pich S. Bach D. Briones P. Liesa M. Camps M. Testar X. Palacin M. Zorzano A. Hum. Mol. Genet. 2005; 14: 1405-1415Crossref PubMed Scopus (331) Google Scholar). Fourth, it was also shown that cytosolic Bax plays a specific role in the steady state activity of Mfn2 as a regulator of mitochondrial fusion (16Karbowski M. Norris K.L. Cleland M.M. Jeong S.Y. Youle R.J. Nature. 2006; 443: 658-662Crossref PubMed Scopus (520) Google Scholar). Most importantly, Mfn2 seems to be critical for the function of the nervous system as point mutations in this molecule have been associated with Charcot Marie Tooth neuropathy type 2A (17Zuchner S. Mersiyanova I.V. M. N. J. M. A. J. Y. O. Y. S. A. J.M. J.M. Genet. 2004; PubMed Scopus Google Scholar). the role of mitofusin 2 in to neuronal injury is for of of the importance of Mfn2 in fusion as as its importance in the nervous we whether Mfn2 is involved in the regulation of injury cerebellar granule neurons. examine the role of this GTPase in apoptosis we have type and a hydrolysis-deficient mutant of Mfn2, Mfn2RasG12V M. R. S. P. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar), and Mfn2RasG12V for of these neurons. We whether Mfn2 neurons against different mechanisms of injury and whether this protection is by mitochondrial fusion and the morphological or through an additional role for Mfn2 that is distinct the of mitochondrial fusion. The of demonstrate that mitochondrial fragmentation in to neuronal injury is and as an early we that Mfn2 mitochondrial fusion in neurons and against neuronal death. that the activation of mitochondrial fusion by expression of Mfn2 or Mfn2RasG12V an equally increase in the mitochondrial to the Interestingly, type Mfn2 and Mfn2RasG12V in the lengthening of mitochondria, the Mfn2RasG12V is most against neuronal cell death and release of These findings a signaling role for Mfn2 that goes beyond its role in the regulation of mitochondrial fusion. and granule neurons at or as A. N. E.S. A. F. K. J. Cell Biol. 2001; PubMed Scopus Google Scholar). ornithine carbamyl mitofusin 2 or its expression as S. J. B. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). Mfn2 was a Zorzano (14Bach D. Pich S. Soriano F.X. Vega N. Baumgartner B. Oriola J. Daugaard J.R. Lloberas J. Camps M. Zierath J.R. Rabasa-Lhoret R. Wallberg-Henriksson H. Laville M. Palacin M. Vidal H. Rivera F. Brand M. Zorzano A. J. Biol. Chem. 2003; 278: 17190-17197Abstract Full Text Full Text PDF PubMed Scopus (637) Google Scholar). at the of with different multiplicity of to was on the and low the and of was 2 days for and the of in these with a the of the with and the of was with the of in the the of was with the of in the Cell death was by by or was used to the of as A. F. J. Cell Biol. 2002; PubMed Scopus Google Scholar). In three to different a with a and The of in was Cell death was as a of DNA K+ and Cell in vitro DNA cell death, with following 2 days in vitro was used to cell death. with following 2 for which the was with the with of of the used in was to and was used to cell death following of K+ cell death, neurons at the of with and days in vitro the K+ was to a low of and with cytochrome and following with or For a of neurons different In a of the was for a cytochrome or of was as on with with and with the ornithine carbamyl a mitochondrial at the of neurons to mitochondria in The in a in with and with an on an by The was with of a the was with the of green and the was with the of shown demonstrate that are of and that have been at least three neurons for with in phosphate-buffered and with with of in for with the in for 1 The with with the secondary to either a PubMed Scopus Google or cytochrome in for 1 The for and with for neurons with for and a with a and Mitochondrial cell by at with the Mitochondrial was by the mitochondria Mitochondrial in neurons. For mitochondria different with a and and cell death a of was for at the For mitochondrial a of mitochondria for was The the and three where for of and or was significant and was on the by an Mitochondrial DNA has been that mitochondria following neuronal injury A.J. J. 2003; PubMed Google Scholar). We whether mitochondria fragmentation or remodeling following DNA neuronal death. The DNA damage induced by following or and is to to the extensive neuronal loss injury L. Mol. PubMed Scopus Google Scholar). in vitro DNA cell death, cerebellar granule neurons with This of was shown to a cell death in neuronal loss by mitochondria in we the of ornithine carbamyl to R. H. Biol. 2004; 14: Full Text Full Text PDF PubMed Google Scholar), and the at the of Mitochondrial dynamics the first We the and of mitochondrial fragmentation following with and with a mitochondrial PubMed Scopus Google and to cell at different following in neurons variable The different to of mitochondrial that following to of mitochondria a of as in the neurons Of these a of between 1 and 2 and a of following with of the mitochondria fragmented with a of of there was a in where of mitochondria a of The fragmentation was by where of mitochondria a of of mitochondria a of at These demonstrate that mitochondrial fragmentation is following of neurons to and there is a difference in the mitochondria by whether this in was because of mitochondrial we a of mitochondria with In mitochondria to of with we did mitochondrial we also mitochondrial fission and whether mitochondrial fragmentation with the cell death, the rate of cell death was by the of of apoptosis following of Cell death to at and was at the on these we that mitochondrial fragmentation is to the of the following DNA cell death. Mitochondrial an of neuronal injury as a of death is the to ROS, which a complex signaling cascade K. J.R. J. Dev. 2004; PubMed Scopus Google Scholar). We whether mitochondrial fragmentation also following oxidative with at the of and with for which the was by that mitochondria fragmentation 1 following 2A and also to to following This of mitochondrial remodeling following fission was a event in this mode of cell death and of neurons to for resulted directly in mitochondrial remodeling first and This was to as of neurons following first 2 of Interestingly, with where the fragmented mitochondria the of fragmented mitochondria was with and 1 and the and fragmentation of mitochondria and its to cell death, mitochondrial and following to ROS, of mitochondria a of with of mitochondrial fragmentation as early as where of mitochondria a of Mitochondrial fragmentation to increase to and at and whether the of mitochondrial fragmentation with cell death, apoptosis was by to The of cell death not following of neurons whereas cell death was by of neurons These that mitochondrial fragmentation was and the apoptotic These findings suggest that mitochondrial fragmentation may as an early apoptotic signaling event in this mode of fragmentation following oxidative with at 2 as in the to shows of mitochondria at point for and mitochondrial was at the following and to The is on the at different and cell death was at the by by demonstrate that mitochondrial fragmentation is an early event following injury in We whether the fragmentation of the mitochondria by activation of the mitochondrial fusion machinery cell death induced by DNA damage and oxidative of Mfn2 Mitochondrial and against examine whether mitochondrial fusion neurons against cell death, we the wild-type Mfn2 and the mutant Mfn2RasG12V M. R. S. P. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). neurons to to oxidative stress or DNA We first whether these proteins affect the mitochondrial in neurons. in with Mfn2, or and the mitochondrial was expression a was with neurons with Mfn2 or Mfn2RasG12V In neurons and the of mitochondria an between 1 and 2 expression of or resulted in a significant increase in the of the The of mitochondria as a of of Mfn2 and expression These demonstrate that enhanced activation of Mfn2 in mitochondrial We whether activation of Mfn2 mitochondrial fragmentation and neurons against death induced by neuronal injury. whether activation of Mfn2 neurons against DNA damage, exposed to The mitochondrial and apoptosis following Mitochondrial fragmentation was with or expression of neurons of mitochondria whereas the expression of and resulted in and of mitochondria Interestingly, the of mitochondria a with mitochondria and These that expression of Mfn2 or activation by expression of Mfn2RasG12V equally the of the mitochondria following DNA Most importantly, the of Mfn2 resulted in protection against cell death induced by DNA damage of of neurons in the and this was reduced to in the Mfn2 activation of Mfn2 through of was significantly the type as it reduced cell death to These demonstrate that whereas Mfn2 and Mfn2RasG12V in fusion of mitochondria, the of Mfn2RasG12V shows a increase in protection of these neurons against DNA We whether activation of Mfn2 neurons against injury induced by in with and exposed to and mitochondrial and cell death as expression of or enhanced activation of Mfn2 by of neurons against the and resulted in significantly mitochondrial following with of mitochondria a of in the This to and in the and More importantly, whereas expression of type Mfn2 resulted in an with an of Mfn2RasG12V to a increase in with of relative to in These demonstrate that of Mfn2 prevents the of the mitochondria in to injury and the mitochondrial in neurons. Most importantly, of the of Mfn2 additional protection against death induced by and DNA These highlight a to neuronal injury. Mfn2 against by a critical of the is to the mitochondria intermembrane space where it is the of the outer mitochondria in release of the cytochrome the the release of the of mitochondrial cytochrome remodeling of mitochondria L. S.J. Biochem. 2003; PubMed Scopus Google Scholar, M. J. 2005; PubMed Scopus Google Scholar). We whether mitofusin 2 release of cytochrome following different cell death stimuli. following of the neurons with the neurons and with an against cytochrome of neurons their cytochrome the mitochondria in the The cytochrome release was to in the type mitofusin and to in the Mfn2RasG12V following with Mfn2 and Mfn2RasG12V release of cytochrome to and with at not that activation of mitofusin 2 in of the cytochrome release following DNA damage and ROS, but it the in between type mitofusin 2 and the activated Mfn2RasG12V These findings also have as an of cell death of cytochrome which the function of Mfn2 the apoptotic cascade in neuronal of cell death. of by a Mfn2RasG12V against is a critical of neuronal during F. L. Y. L. B. J. Google Scholar). K+ the and the of the of these can neuronal death or neuronal Y. Dev. 2003; PubMed Scopus Google Scholar). K+ of granule neurons a complex of and mechanisms that of and inhibition of C. J. 2002; PubMed Scopus Google Scholar). it has been recently demonstrated that K+ exhibit an in mitochondrial a in which with Cell Death Differ. 2006; PubMed Scopus Google and of P. C. S. M. A. R. J. 2001; PubMed Scopus Google Scholar). cerebellar granule neurons a for we whether mitofusin 2 against this mode of cell death. We a for the Mfn2RasG12V to The K+ was to the of K+ following and following in the low the of cell death was the The cell death in the to in the Mfn2RasG12V for the cell death in to in Mfn2RasG12V Mfn2RasG12V for a protection against K+ apoptosis Mfn2 of Cell Death in the antiapoptotic role of mitofusin 2 in neuronal we induced by (14Bach D. Pich S. Soriano F.X. Vega N. Baumgartner B. Oriola J. Daugaard J.R. Lloberas J. Camps M. Zierath J.R. Rabasa-Lhoret R. Wallberg-Henriksson H. Laville M. Palacin M. Vidal H. Rivera F. Brand M. Zorzano A. J. Biol. Chem. 2003; 278: 17190-17197Abstract Full Text Full Text PDF PubMed Scopus (637) Google of of neuronal was by that neurons exhibit a significant cell death, with at in the neurons in the absence of any cell death stimuli. The of a of first we that mitochondrial fragmentation as an early event in to injury in cerebellar granule neurons. The extent of mitochondrial is variable and depends on the mode of neuronal injury and the severity of the death stimuli. Second, expression of Mfn2 prevents mitochondrial fragmentation in to oxidative stress and DNA neuronal death. Third, we that in to the fusion machinery, Mfn2 neurons against different modes of neuronal injury DNA damage, oxidative stress, and apoptosis. Most importantly, we demonstrate that the type Mfn2 and the activated mutant Mfn2RasG12V function equally to promote fusion and lengthening of mitochondria, neuronal protection against injury is in the GTPase hydrolysis-deficient Mfn2 mutant the type mitofusin 2 its at an early of cytochrome of mitofusin 2 induces cell death in the absence of any apoptotic stimuli. these findings an role for Mfn2 during death of neuronal injury and neuronal Mfn2 has been to function along with its Mfn1 as a 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 (1706) Google Scholar, N. Eura Y. Mihara K. J. Cell Sci. 2004; 117: 6535-6546Crossref PubMed Scopus (492) Google Scholar), that the activation of mitochondrial fusion by expression of Mfn2 or Mfn2RasG12V a increase in the mitochondrial to This neuronal a lengthening of the mitochondria is that in cell where the expression of Mfn2 resulted in mitochondria fusion a M. R. S. P. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). may be in their to to these and may a distinct of proteins that mitochondrial fusion relative to cell is whether the mitochondria are of the fragmented mitochondria or involved in the fusion machinery interact with cell death have demonstrated that fusion by of Mfn1 or a mutant of Drp1 against cell death H. Y. S. Lee J. J. B. Martinou J.C. Youle R.J. S.A. J. 2006; PubMed Scopus Google Scholar). Mfn1, which with Opa1 to Mfn2 has been associated with apoptotic signaling proteins (16Karbowski M. Norris K.L. Cleland M.M. Jeong S.Y. Youle R.J. Nature. 2006; 443: 658-662Crossref PubMed Scopus (520) Google Scholar, M. R. S. P. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). Interestingly, we that expression of the type Mfn2 and the on mitochondrial the hydrolysis-deficient mutant a protection against cell death. These distinct suggest that the protection death may not be to the fusion because the type and mutant Mfn2 in in mitochondrial the suggest that the nucleotide state of Mfn2 may on the mitochondrial that are critical for the cell death. supporting an additional role for Mfn2 beyond the activation of fusion is with findings that demonstrate with the Bcl family Mfn2 is colocalized in punctate with Bax and Drp1 at sites of future fission and mitochondrial recruitment of Bax or Drp1 during cell death, a relationship between fusion and fission during cell death (13Karbowski M. Lee Y.J. Gaume B. Jeong S.Y. Frank S. Nechushtan A. Santel A. Fuller M. Smith C.L. Youle R.J. J. Cell Biol. 2002; 159: 931-938Crossref PubMed Scopus (658) Google Scholar). Second, it was shown that cytosolic Bax plays a specific role in the steady state activity of Mfn2 as a regulator of mitochondrial fusion (16Karbowski M. Norris K.L. Cleland M.M. Jeong S.Y. Youle R.J. Nature. 2006; 443: 658-662Crossref PubMed Scopus (520) Google Scholar). In that the mitochondria the demonstrated a reduced rate of mitochondrial fusion. Mfn2 is in a punctate M. R. S. P. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google in cells, the the outer (16Karbowski M. Norris K.L. Cleland M.M. Jeong S.Y. Youle R.J. Nature. 2006; 443: 658-662Crossref PubMed Scopus (520) Google Scholar). The of Bax the resulted in a shift of Mfn2 the outer mitochondrial which the of fusion. Interestingly, the of Mfn2 did not to expression and its along the outer of expression (16Karbowski M. Norris K.L. Cleland M.M. Jeong S.Y. Youle R.J. Nature. 2006; 443: 658-662Crossref PubMed Scopus (520) Google Scholar). that this mutant was not by it is that Mfn2RasG12V is also to on the during apoptotic stimuli. This of Mfn2RasG12V to may with the of proapoptotic for the of cell death. This would at least the of the activated mutant to apoptotic that we have in neurons. Mfn2 can interact directly with Ced9 or in HEK293 suggesting a mechanism for cross-talk with antiapoptotic Bcl family proteins (3Delivani P. Adrain C. Taylor R.C. Duriez P.J. Martin S.J. Mol. Cell. 2006; 21: 761-773Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar). Mfn2 have not been shown to be reduced during the nucleotide state of Mfn2 be to with the apoptotic We a the of Mfn2 may interact with the family of along the outer in a and against cell death. In the would be to by Bax to and of the death machinery on the outer be to this activity is regulated in the context of the apoptosis signaling there is evidence to the that the that mitochondrial fusion are to the the For example, Mfn2 has been shown to modulate metabolism through function of complex 1, IV, and V (14Bach D. Pich S. Soriano F.X. Vega N. Baumgartner B. Oriola J. Daugaard J.R. Lloberas J. Camps M. Zierath J.R. Rabasa-Lhoret R. Wallberg-Henriksson H. Laville M. Palacin M. Vidal H. Rivera F. Brand M. Zorzano A. J. Biol. Chem. 2003; 278: 17190-17197Abstract Full Text Full Text PDF PubMed Scopus (637) Google Scholar, 15Pich S. Bach D. Briones P. Liesa M. Camps M. Testar X. Palacin M. Zorzano A. Hum. Mol. Genet. 2005; 14: 1405-1415Crossref PubMed Scopus (331) Google Scholar). with this of fusion proteins and to fragmented mitochondria with reduced oxygen and H. A. Chan D.C. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). This suggests that mitochondrial fusion is to be a central in mitochondrial dynamics to mitochondrial and also be a mechanism for cell death during neuronal injury. In we that mitochondria extensive fragmentation in neuronal injury and that the mitochondrial fusion machinery can neurons against injury induced cell death. These demonstrate the importance of mitochondrial dynamics in as and that the of the nucleotide state of Mfn2 can affect the of cell death suggests that Mfn2 may as an for the of these to investigate the that the nucleotide state of Mfn2 and to the with the apoptotic machinery these We Zorzano of for of We also and for the critical of this The is by a the R. S. S. and D. S. with

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