线粒体融合与分裂的分子机制及相关疾病的研究进展
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摘要
线粒体是细胞能量代谢的中心,线粒体的网格形态可通过其融合与分裂而处于一种动态的变化中,以此适应不同环境下的能量需求。线粒体融合蛋白Mitofusin1/2(Mfn1/2),视神经萎缩蛋白(OPA1)和线粒体分裂蛋白(Drp1)分别在线粒体的融合和分裂过程中起到了关键的调节作用。而线粒体融合与分裂功能的异常,参与了人体各个系统许多损伤过程,包括视神经萎缩、缺血再灌注损伤等。本文将回顾上述几种关键蛋白为代表的线粒体融合与分裂关键调控分子、调节机制以及其异常所造成的疾病。
Mitochondria is the center of cellular energy metabolism, and the mitochondrial network maintains a dynamic balance through its fusion and fission, so as to adapt to the energy requirements of cells under different environmental conditions. Mitofusin 1/2(Mfn1/2), optic atrophy proteins(OPA1) and Dynamin-1 like protein(Drp1) play key roles in the process of mitochondrial fusion and fission, respectively. The abnormality of mitochondrial fusion and fission function is involved in the progress of many diseases and pathological changes in various systems of the human body, including optic atrophy and ischemia/reperfusion injury. This article will review the key molecules including their mechanism in regulating mitochondrial fusion and fission and the diseases related to their dysfunctions.
Mitochondria is the center of cellular energy metabolism, and the mitochondrial network maintains a dynamic balance through its fusion and fission, so as to adapt to the energy requirements of cells under different environmental conditions. Mitofusin 1/2(Mfn1/2), optic atrophy proteins(OPA1) and Dynamin-1 like protein(Drp1) play key roles in the process of mitochondrial fusion and fission, respectively. The abnormality of mitochondrial fusion and fission function is involved in the progress of many diseases and pathological changes in various systems of the human body, including optic atrophy and ischemia/reperfusion injury. This article will review the key molecules including their mechanism in regulating mitochondrial fusion and fission and the diseases related to their dysfunctions.
引文
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[18]Biel TG,Lee S,Flores-Toro JA,et al.Sirtuin 1 suppresses mitochondrial dysfunction of ischemic mouse livers in a mitofusin 2-dependent manner[J].Cell Death Differ,2016,23:279-290.
[19]Cao YL,Meng S,Chen Y,et al.MFN1 structures reveal nucleotide-triggered dimerization critical for mitochondrial fusion[J].Nature,2017,542:372-376.
[20]Landes T,Emorine LJ,Courilleau D,et al.The BH3-only Bnip3 binds to the dynamin Opa1 to promote mitochondrial fragmentation and apoptosis by distinct mechanisms[J].EMBO Rep,2010,11:459-465.
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[23]Zhang Y,Chan DC.Structural basis for recruitment of mitochondrial fission complexes by Fis1[J].Proc Natl Acad Sci U S A,2007,104:18 526-18 530.
[24]Otera H,Wang C,Cleland MM,et al.Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells[J].J Cell Biol,2010,191:1 141-1 158.
[25]Palmer CS,Osellame LD,Laine D,et al.MiD49 and MiD51,new components of the mitochondrial fission machinery[J].EMBO Rep,2011,12:565-573.
[26]Tondera D,Czauderna F,Paulick K,et al.The mitochondrial protein MTP18 contributes to mitochondrial fission in mammalian cells[J].J Cell Sci,2005,118:3 049-3 059.
[27]Karbowski M,Jeong SY,Youle RJ.Endophilin B1 is required for the maintenance of mitochondrial morphology[J].J Cell Biol,2004,166:1 027-1 039.
[28]Pagliuso A,Cossart P,Stavru F.The ever-growing complexity of the mitochondrial fission machinery[J].Cell Mol Life Sci,2018,75(3):355-374.
[29]Nakamura T,Cieplak P,Cho DH,et al.S-nitrosylation of Drp1 links excessive mitochondrial fission to neuronal injury in neurodegeneration[J].Mitochondrion,2010,10:573-578.
[30]Nagashima S,Tokuyama T,Yonashiro R,et al.Roles of mitochondrial ubiquitin ligase MITOL/MARCH5 in mitochondrial dynamics and diseases[J].J Biochem,2014,155:273-279.
[31]Buhlman L,Damiano M,Bertolin G,et al.Functional interplay between Parkin and Drp1 in mitochondrial fission and clearance[J].Biochim Biophys Acta,2014,1 843:2 012-2 026.
[32]Braschi E,Zunino R,McBride HM.MAPL is a new mitochondrial SUMO E3 ligase that regulates mitochondrial fission[J].EMBO Rep,2009,10:748-754.
[33]Zunino R,Schauss A,Rippstein P,et al.The SUMOprotease SENP5 is required to maintain mitochondrial morphology and function[J].J Cell Sci,2007,120:1 178-1 188.
[34]Schrepfer E,Scorrano L.Mitofusins,from mitochondria to metabolism[J].Mol Cell,2016,61(5):683-694.
[35]Stuppia G,Rizzo F,Riboldi G,et al.MFN2-related neuropathies:Clinical features,molecular pathogenesis and therapeutic perspectives[J].J Neurol Sci,2015,356:7-18.
[36]Zhang R,Zhou H,Jiang L,et al.MiR-195 dependent roles of mitofusin2 in the mitochondrial dysfunction of hippocampal neurons in SAMP8 mice[J].Brain Res,2016,1 652:135-143.
[37]Davies VJ,Hollins AJ,Piechota MJ,et al.Opa1 deficiency in a mouse model of autosomal dominant optic atrophy impairs mitochondrial morphology,optic nerve structure and visual function[J].Hum Mol Genet,2007,16:1 307-1 318.
[2]Hoppins S,Edlich F,Cleland MM,et al.The soluble form of Bax regulates mitochondrial fusion via MFN2homotypic complexes[J].Mol Cell,2011,41:150-160.
[3]Eura Y,Ishihara N,Yokota S,et al.Two mitofusin proteins,mammalian homologues of FZO,with distinct functions are both required for mitochondrial fusion[J].J Biochem,2003,134:333-344.
[4]Wang W,Xie Q,Zhou X,et al.Mitofusin-2 triggers mitochondria Ca2+influx from the endoplasmic reticulum to induce apoptosis in hepatocellular carcinoma cells[J].Cancer Lett,2015,358:47-58.
[5]Satoh M,Hamamoto T,Seo N,et al.Differential sublocalization of the dynamin-related protein OPA1 isoforms in mitochondria[J].Biochem Biophys Res Commun,2003,300:482-493.
[6]Gerber S,Charif M,Chevrollier A,et al.Mutations in DNM1L,as in OPA1,result in dominant optic atrophy despite opposite effects on mitochondrial fusion and fission[J].Brain,2017,140(10):2 586-2 596.
[7]Pernas L,Scorrano L.Mito-Morphosis:mitochondrial fusion,fission,and cristae remodeling as key mediators of cellular function[J].Annu Rev Physiol,2016,78:505-531.
[8]Ding Y,Gao H,Zhao L,et al.Mitofusin 2-deficiency suppresses cell proliferation through disturbance of autophagy[J].PLoS One,2015,10:e0121328.
[9]Chen Y,Dorn GW.PINK1-phosphorylated mitofusin 2is a Parkin receptor for culling damaged mitochondria[J].Science,2013,340:471-475.
[10]Chen KH,Dasgupta A,Ding J,et al.Role of mitofusin 2(Mfn2)in controlling cellular proliferation[J].FASEB J,2014,28:382-394.
[11]Leboucher GP,Tsai YC,Yang M,et al.Stress-induced phosphorylation and proteasomal degradation of mitofusin 2 facilitates mitochondrial fragmentation and apoptosis[J].Mol Cell,2012,47:547-557.
[12]Nakamura N,Kimura Y,Tokuda M,et al.MARCH-V is a novel mitofusin 2-and Drp1-binding protein able to change mitochondrial morphology[J].EMBO Rep,2006,7:1 019-1 022.
[13]Saito T,Sadoshima J.Molecular mechanisms of mitochondrial autophagy/mitophagy in the heart[J].Circ Res,2015,116:1 477-1 490.
[14]Liesa M,Borda-d'Agua B,Medina-Gómez G,et al.Mitochondrial fusion is increased by the nuclear coactivator PGC-1beta[J].PLoS One,2008,3:e3613.
[15]Soriano FX,Liesa M,Bach D,et al.Evidence for a mitochondrial regulatory pathway defined by peroxisome proliferator-activated receptor-gamma coactivator-1 alpha,estrogen-related receptor-alpha,and mitofusin2[J].Diabetes,2006,55:1 783-1 791.
[16]Karbowski M,Norris KL,Cleland MM,et al.Role of Bax and Bak in mitochondrial morphogenesis[J].Nature,2006,443:658-662.
[17]Kumar S,Pan CC,Shah N,et al.Activation of mitofusin2 by Smad2-RIN1 complex during mitochondrial fusion[J].Mol Cell,2016,62:520-531.
[18]Biel TG,Lee S,Flores-Toro JA,et al.Sirtuin 1 suppresses mitochondrial dysfunction of ischemic mouse livers in a mitofusin 2-dependent manner[J].Cell Death Differ,2016,23:279-290.
[19]Cao YL,Meng S,Chen Y,et al.MFN1 structures reveal nucleotide-triggered dimerization critical for mitochondrial fusion[J].Nature,2017,542:372-376.
[20]Landes T,Emorine LJ,Courilleau D,et al.The BH3-only Bnip3 binds to the dynamin Opa1 to promote mitochondrial fragmentation and apoptosis by distinct mechanisms[J].EMBO Rep,2010,11:459-465.
[21]Tilokani L,Nagashima S,Paupe V,et al.Mitochondrial dynamics:overview of molecular mechanisms[J].Essays Biochem,2018,62(3):341-360.
[22]Westermann B.Mitochondrial fusion and fission in cell life and death[J].Nat Rev Mol Cell Biol,2010,11:872-884.
[23]Zhang Y,Chan DC.Structural basis for recruitment of mitochondrial fission complexes by Fis1[J].Proc Natl Acad Sci U S A,2007,104:18 526-18 530.
[24]Otera H,Wang C,Cleland MM,et al.Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells[J].J Cell Biol,2010,191:1 141-1 158.
[25]Palmer CS,Osellame LD,Laine D,et al.MiD49 and MiD51,new components of the mitochondrial fission machinery[J].EMBO Rep,2011,12:565-573.
[26]Tondera D,Czauderna F,Paulick K,et al.The mitochondrial protein MTP18 contributes to mitochondrial fission in mammalian cells[J].J Cell Sci,2005,118:3 049-3 059.
[27]Karbowski M,Jeong SY,Youle RJ.Endophilin B1 is required for the maintenance of mitochondrial morphology[J].J Cell Biol,2004,166:1 027-1 039.
[28]Pagliuso A,Cossart P,Stavru F.The ever-growing complexity of the mitochondrial fission machinery[J].Cell Mol Life Sci,2018,75(3):355-374.
[29]Nakamura T,Cieplak P,Cho DH,et al.S-nitrosylation of Drp1 links excessive mitochondrial fission to neuronal injury in neurodegeneration[J].Mitochondrion,2010,10:573-578.
[30]Nagashima S,Tokuyama T,Yonashiro R,et al.Roles of mitochondrial ubiquitin ligase MITOL/MARCH5 in mitochondrial dynamics and diseases[J].J Biochem,2014,155:273-279.
[31]Buhlman L,Damiano M,Bertolin G,et al.Functional interplay between Parkin and Drp1 in mitochondrial fission and clearance[J].Biochim Biophys Acta,2014,1 843:2 012-2 026.
[32]Braschi E,Zunino R,McBride HM.MAPL is a new mitochondrial SUMO E3 ligase that regulates mitochondrial fission[J].EMBO Rep,2009,10:748-754.
[33]Zunino R,Schauss A,Rippstein P,et al.The SUMOprotease SENP5 is required to maintain mitochondrial morphology and function[J].J Cell Sci,2007,120:1 178-1 188.
[34]Schrepfer E,Scorrano L.Mitofusins,from mitochondria to metabolism[J].Mol Cell,2016,61(5):683-694.
[35]Stuppia G,Rizzo F,Riboldi G,et al.MFN2-related neuropathies:Clinical features,molecular pathogenesis and therapeutic perspectives[J].J Neurol Sci,2015,356:7-18.
[36]Zhang R,Zhou H,Jiang L,et al.MiR-195 dependent roles of mitofusin2 in the mitochondrial dysfunction of hippocampal neurons in SAMP8 mice[J].Brain Res,2016,1 652:135-143.
[37]Davies VJ,Hollins AJ,Piechota MJ,et al.Opa1 deficiency in a mouse model of autosomal dominant optic atrophy impairs mitochondrial morphology,optic nerve structure and visual function[J].Hum Mol Genet,2007,16:1 307-1 318.