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DOI | 10.1126/science.aao1785 |
MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A | |
Rocha, Agostinho G.1; Franco, Antonietta1; Krezel, Andrzej M.2; Rumsey, Jeanne M.1; Alberti, Justin M.1; Knight, William C.1; Biris, Nikolaos3,4; Zacharioudakis, Emmanouil3,4; Janetka, James W.2; Baloh, Robert H.5; Kitsis, Richard N.4,6,7; Mochly-Rosen, Daria8; Townsend, R. Reid1; Gavathiotis, Evripidis3,4; Dorn, Gerald W., II1 | |
2018-04-20 | |
发表期刊 | SCIENCE |
ISSN | 0036-8075 |
EISSN | 1095-9203 |
出版年 | 2018 |
卷号 | 360期号:6386页码:336-341 |
文章类型 | Article |
语种 | 英语 |
国家 | USA |
英文摘要 | Mitofusins (MFNs) promote fusion-mediated mitochondrial content exchange and subcellular trafficking. Mutations in Mfn2 cause neurodegenerative Charcot-Marie-Tooth disease type 2A (CMT2A). We showed that MFN2 activity can be determined by Met(376) and His(380) interactions with Asp(725) and Leu(727) and controlled by PINK1 kinase-mediated phosphorylation of adjacent MFN2 Ser(378). Small-molecule mimics of the peptide-peptide interface of MFN2 disrupted this interaction, allosterically activating MFN2 and promoting mitochondrial fusion. These first-in-class mitofusin agonists overcame dominant mitochondrial defects provoked in cultured neurons by CMT2A mutants MFN2 Arg(94)-> Gln(94) and MFN2 Thr(105)-> Met(105), as demonstrated by amelioration of mitochondrial dysmotility, fragmentation, depolarization, and clumping. A mitofusin agonist normalized axonal mitochondrial trafficking within sciatic nerves of MFN2 Thr(105)-> Met(105) mice, promising a therapeutic approach for CMT2A and other untreatable diseases of impaired neuronal mitochondrial dynamism and/or trafficking. |
领域 | 地球科学 ; 气候变化 ; 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000430396600049 |
WOS关键词 | MUTATIONS ; TRANSPORT ; DYNAMICS ; FEATURES ; FUSION ; HEALTH |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/198466 |
专题 | 地球科学 资源环境科学 气候变化 |
作者单位 | 1.Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA; 2.Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA; 3.Albert Einstein Coll Med, Albert Einstein Canc Ctr, Wilf Family Cardiovasc Res Inst, Dept Biochem, Bronx, NY 10467 USA; 4.Albert Einstein Coll Med, Albert Einstein Canc Ctr, Wilf Family Cardiovasc Res Inst, Dept Med, Bronx, NY 10467 USA; 5.Cedars Sinai Med Ctr, Dept Neurol, Los Angeles, CA 90048 USA; 6.Albert Einstein Coll Med, Albert Einstein Canc Ctr, Wilf Family Cardiovasc Res Inst, Dept Cell Biol, Bronx, NY 10467 USA; 7.Albert Einstein Coll Med, Einstein Mt Sinai Diabet Res Ctr, Bronx, NY 10467 USA; 8.Stanford Univ, Sch Med, Dept Chem & Syst Biol, Stanford, CA 94305 USA |
推荐引用方式 GB/T 7714 | Rocha, Agostinho G.,Franco, Antonietta,Krezel, Andrzej M.,et al. MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A[J]. SCIENCE,2018,360(6386):336-341. |
APA | Rocha, Agostinho G..,Franco, Antonietta.,Krezel, Andrzej M..,Rumsey, Jeanne M..,Alberti, Justin M..,...&Dorn, Gerald W., II.(2018).MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A.SCIENCE,360(6386),336-341. |
MLA | Rocha, Agostinho G.,et al."MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A".SCIENCE 360.6386(2018):336-341. |
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