MFN2调控线粒体动态变化的研究进展
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摘要
线粒体通过自噬清除受损或多余线粒体以维持线粒体稳态。线粒体分裂融合是线粒体自噬的基础,线粒体融合蛋白-2(MFN2)参与调节线粒体分裂融合。MFN2突变会引起线粒体功能障碍,导致腓骨肌萎缩等神经退行性疾病。本文主要综述了近年来MFN2功能及其在线粒体自噬及神经退行性疾病领域所取得的研究进展,旨在为相关领域进一步的研究提供参考。
To maintain mitochondria homeostasis, mitochondria remove damaged or excess mitochondria by autophagy.Mitochondria fission and fusion process is the basis of mitophagy, and mitofusion-2(MFN2) is involved in the process of regulating mitochondria fission and fusion. Mutations in MFN2 could cause mitochondria dysfunction and even lead to neurodegenerative diseases such as Charcot-Marie-Tooth. This paper review recent research progress of MFN2 function and its effect on mitochondria autophagy and neurodegenerative disease, aiming at providing reference for further research in related fields.
To maintain mitochondria homeostasis, mitochondria remove damaged or excess mitochondria by autophagy.Mitochondria fission and fusion process is the basis of mitophagy, and mitofusion-2(MFN2) is involved in the process of regulating mitochondria fission and fusion. Mutations in MFN2 could cause mitochondria dysfunction and even lead to neurodegenerative diseases such as Charcot-Marie-Tooth. This paper review recent research progress of MFN2 function and its effect on mitochondria autophagy and neurodegenerative disease, aiming at providing reference for further research in related fields.
引文
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[5]Ishihara N,Eura Y,Mihara K.Mitofusin 1 and 2 play distinct roles in mitochondrial fusion reactions via GTPase activity[J].J Cell Sci,2004,117(Pt 26):6535-6546.
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[9]Cao YL,Meng S,Chen Y,et al.MFN1 structures reveal nucleotide-triggered dimerization critical for mitochondrial fusion[J].Nature,2017,542(7641):372-376.
[10]Chen H,Detmer SA,Ewald AJ,et al.Mitofusins Mfn1and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development[J].J Cell Biol,2003,160(2):189-200.
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[14]Sebastian D,Hernandez-Alvarez MI,Segales J,et al.Mitofusin 2(Mfn2)links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis[J].Proc Natl Acad Sci US A,2012,109(14):5523-5528.
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[17]Ding Y,Gao H,Zhao L,et al.Mitofusin 2-deficiency suppresses cell proliferation through disturbance of autophagy[J].PLoS One,2015,10(3):e0121328.
[18]Shen T,Zheng M,Cao C,et al.Mitofusin-2 is a major determinant of oxidative stress-mediated heart muscle cell apoptosis[J].J Biol Chem,2007,282(32):23 354-23 361.
[19]Parra V,Eisner V,Chiong M,et al.Changes in mitochondrial dynamics during ceramide-induced cardiomyocyte early apoptosis[J].Cardiovasc Res,2008,77(2):387-397.
[20]de Brito OM,Scorrano L.Mitofusin 2 tethers endoplasmic reticulum to mitochondria[J].Nature,2008,456(7222):605-610.
[21]Bidaux G,Gordienko D,Shapovalov G,et al.4TM-TRPM8channels are new gatekeepers of the ER-mitochondria Ca(2+)transfer[J].Biochim Biophys Acta,2018,1865(7):981-994.
[22]Filadi R,Greotti E,Turacchio G,et al.Mitofusin 2 ablation increases endoplasmic reticulum-mitochondria coupling[J].Proc Natl Acad Sci U S A,2015,112(17):E2174-E2181.
[23]Vigie P,Camougrand N.[Role of mitophagy in the mitochondrial quality control][J].Med Sci(Paris),2017,33(3):231-237.
[24]Eiyama A,Okamoto K.PINK1/Parkin-mediated mitophagy in mammalian cells[J].Curr Opin Cell Biol,2015,33:95-101.
[25]Harper JW,Ordureau A,Heo JM.Building and decoding ubiquitin chains for mitophagy[J].Nat Rev Mol Cell Biol,2018,19(2):93-108.
[26]Chen Y,Dorn GW.PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria[J].Science,2013,340(6131):471-475.
[27]Leboucher GP,Tsai YC,Yang M,et al.Stress-induced phosphorylation and proteasomal degradation of mitofusin2 facilitates mitochondrial fragmentation and apoptosis[J].Mol Cell,2012,47(4):547-557.
[28]Zhao T,Huang X,Han L,et al.Central role of mitofusin2 in autophagosome-lysosome fusion in cardiomyocytes[J].J Biol Chem,2012,287(28):23 615-23 625.
[29]Peng C,Rao W,Zhang L,et al.Mitofusin 2 Exerts a Protective Role in Ischemia Reperfusion Injury Through Increasing Autophagy[J].Cell Physiol Biochem,2018,46(6):2311-2324.
[30]McLelland GL,Goiran T,Yi W,et al.Mfn2 ubiquitination by PINK1/parkin gates the p97-dependent release of ER from mitochondria to drive mitophagy[J].Elife,2018,7:e32866.
[31]Zhao F,Wang W,Wang C,et al.Mfn2 protects dopaminergic neurons exposed to paraquat both in vitro and in vivo:Implications for idiopathic Parkinson′s disease[J].Biochim Biophys Acta,2017,1863(6):1359-1370.
[32]Xi Y,Feng D,Tao K,et al.MitoQ protects dopaminergic neurons in a 6-OHDA induced PD model by enhancing Mfn2-dependent mitochondrial fusion via activation of PGC-1alpha[J].Biochim Biophys Acta,2018,1864(9):2859-2870.
[33]Xie Y,Li X,Liu L,et al.MFN2-related genetic and clinical features in a cohort of Chinese CMT2 patients[J].JPeripher Nerv Syst,2016,21(1):38-44.
[34]Beresewicz M,Boratynska-Jasinska A,Charzewski L,et al.The Effect of a Novel c.820C>T(Arg274Trp)Mutation in the Mitofusin 2 Gene on Fibroblast Metabolism and Clinical Manifestation in a Patient[J].PLoS One,2017,12(1):e0169999.
[35]Dankwa L,Richardson J,Motley WW,et al.A mutation in the heptad repeat 2 domain of MFN2 in a large CMT2Afamily[J].J Peripher Nerv Syst,2018,23(1):36-39.
[36]Franco A,Kitsis RN,Fleischer JA,et al.Correcting mitochondrial fusion by manipulating mitofusin conformations[J]Nature,2016,540(7631):74-79.
[37]Rocha AG,Franco A,Krezel AM,et al.MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A[J].Science,2018,360(6386):336-341.
[2]Rodolfo C,Campello S,Cecconi F.Mitophagy in neurodegenerative diseases[J].Neurochem Int,2018,117:156-166.
[3]Santel A,Frank S,Gaume B,et al.Mitofusin-1 protein is a generally expressed mediator of mitochondrial fusion in mammalian cells[J].J Cell Sci,2003,116(Pt 13):2763-2774.
[4]Bourne HR,Sanders DA,McCormick F.The GTPase superfamily:conserved structure and molecular mechanism[J].Nature,1991,349(6305):117-127.
[5]Ishihara N,Eura Y,Mihara K.Mitofusin 1 and 2 play distinct roles in mitochondrial fusion reactions via GTPase activity[J].J Cell Sci,2004,117(Pt 26):6535-6546.
[6]Daste F,Sauvanet C,Bavdek A,et al.The heptad repeat domain 1 of Mitofusin has membrane destabilization function in mitochondrial fusion[J].EMBO Rep,2018,19(6).pii:e43637.
[7]Koshiba T,Detmer SA,Kaiser JT,et al.Structural basis of mitochondrial tethering by mitofusin complexes[J].Science,2004,305(5685):858-862.
[8]Meeusen S,McCaffery JM,Nunnari J.Mitochondrial fusion intermediates revealed in vitro[J].Science,2004,305(5691):1747-1752.
[9]Cao YL,Meng S,Chen Y,et al.MFN1 structures reveal nucleotide-triggered dimerization critical for mitochondrial fusion[J].Nature,2017,542(7641):372-376.
[10]Chen H,Detmer SA,Ewald AJ,et al.Mitofusins Mfn1and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development[J].J Cell Biol,2003,160(2):189-200.
[11]Bach D,Pich S,Soriano FX,et al.Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism.A novel regulatory mechanism altered in obesity[J].J Biol Chem,2003,278(19):17 190-17 197.
[12]Pich S,Bach D,Briones P,et al.The Charcot-MarieTooth type 2A gene product,Mfn2,up-regulates fuel oxidation through expression of OXPHOS system[J].Hum Mol Genet,2005,14(11):1405-1415.
[13]Mourier A,Motori E,Brandt T,et al.Mitofusin 2 is required to maintain mitochondrial coenzyme Q levels[J].JCell Biol,2015,208(4):429-442.
[14]Sebastian D,Hernandez-Alvarez MI,Segales J,et al.Mitofusin 2(Mfn2)links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis[J].Proc Natl Acad Sci US A,2012,109(14):5523-5528.
[15]Nie Q,Wang C,Song G,et al.Mitofusin 2 deficiency leads to oxidative stress that contributes to insulin resistance in rat skeletal muscle cells[J].Mol Biol Rep,2014,41(10):6975-6983.
[16]Chen KH,Dasgupta A,Ding J,et al.Role of mitofusin 2(Mfn2)in controlling cellular proliferation[J].FASEB J,2014,28(1):382-394.
[17]Ding Y,Gao H,Zhao L,et al.Mitofusin 2-deficiency suppresses cell proliferation through disturbance of autophagy[J].PLoS One,2015,10(3):e0121328.
[18]Shen T,Zheng M,Cao C,et al.Mitofusin-2 is a major determinant of oxidative stress-mediated heart muscle cell apoptosis[J].J Biol Chem,2007,282(32):23 354-23 361.
[19]Parra V,Eisner V,Chiong M,et al.Changes in mitochondrial dynamics during ceramide-induced cardiomyocyte early apoptosis[J].Cardiovasc Res,2008,77(2):387-397.
[20]de Brito OM,Scorrano L.Mitofusin 2 tethers endoplasmic reticulum to mitochondria[J].Nature,2008,456(7222):605-610.
[21]Bidaux G,Gordienko D,Shapovalov G,et al.4TM-TRPM8channels are new gatekeepers of the ER-mitochondria Ca(2+)transfer[J].Biochim Biophys Acta,2018,1865(7):981-994.
[22]Filadi R,Greotti E,Turacchio G,et al.Mitofusin 2 ablation increases endoplasmic reticulum-mitochondria coupling[J].Proc Natl Acad Sci U S A,2015,112(17):E2174-E2181.
[23]Vigie P,Camougrand N.[Role of mitophagy in the mitochondrial quality control][J].Med Sci(Paris),2017,33(3):231-237.
[24]Eiyama A,Okamoto K.PINK1/Parkin-mediated mitophagy in mammalian cells[J].Curr Opin Cell Biol,2015,33:95-101.
[25]Harper JW,Ordureau A,Heo JM.Building and decoding ubiquitin chains for mitophagy[J].Nat Rev Mol Cell Biol,2018,19(2):93-108.
[26]Chen Y,Dorn GW.PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria[J].Science,2013,340(6131):471-475.
[27]Leboucher GP,Tsai YC,Yang M,et al.Stress-induced phosphorylation and proteasomal degradation of mitofusin2 facilitates mitochondrial fragmentation and apoptosis[J].Mol Cell,2012,47(4):547-557.
[28]Zhao T,Huang X,Han L,et al.Central role of mitofusin2 in autophagosome-lysosome fusion in cardiomyocytes[J].J Biol Chem,2012,287(28):23 615-23 625.
[29]Peng C,Rao W,Zhang L,et al.Mitofusin 2 Exerts a Protective Role in Ischemia Reperfusion Injury Through Increasing Autophagy[J].Cell Physiol Biochem,2018,46(6):2311-2324.
[30]McLelland GL,Goiran T,Yi W,et al.Mfn2 ubiquitination by PINK1/parkin gates the p97-dependent release of ER from mitochondria to drive mitophagy[J].Elife,2018,7:e32866.
[31]Zhao F,Wang W,Wang C,et al.Mfn2 protects dopaminergic neurons exposed to paraquat both in vitro and in vivo:Implications for idiopathic Parkinson′s disease[J].Biochim Biophys Acta,2017,1863(6):1359-1370.
[32]Xi Y,Feng D,Tao K,et al.MitoQ protects dopaminergic neurons in a 6-OHDA induced PD model by enhancing Mfn2-dependent mitochondrial fusion via activation of PGC-1alpha[J].Biochim Biophys Acta,2018,1864(9):2859-2870.
[33]Xie Y,Li X,Liu L,et al.MFN2-related genetic and clinical features in a cohort of Chinese CMT2 patients[J].JPeripher Nerv Syst,2016,21(1):38-44.
[34]Beresewicz M,Boratynska-Jasinska A,Charzewski L,et al.The Effect of a Novel c.820C>T(Arg274Trp)Mutation in the Mitofusin 2 Gene on Fibroblast Metabolism and Clinical Manifestation in a Patient[J].PLoS One,2017,12(1):e0169999.
[35]Dankwa L,Richardson J,Motley WW,et al.A mutation in the heptad repeat 2 domain of MFN2 in a large CMT2Afamily[J].J Peripher Nerv Syst,2018,23(1):36-39.
[36]Franco A,Kitsis RN,Fleischer JA,et al.Correcting mitochondrial fusion by manipulating mitofusin conformations[J]Nature,2016,540(7631):74-79.
[37]Rocha AG,Franco A,Krezel AM,et al.MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A[J].Science,2018,360(6386):336-341.