https://scholars.lib.ntu.edu.tw/handle/123456789/454665
標題: | Two separate functions of NME3 critical for cell survival underlie a neurodegenerative disorder | 作者: | Chen C.-W. Wang H.-L. Huang C.-W. Huang C.-Y. Lim W.K. Chen Tu I. Koorapati A. SUNG-TSANG HSIEH Kan H.-W. SHIOU-RU TZENG Liao J.-C. Chong W.M. Naroditzky I. Kidron D. Eran A. Nijim Y. Sela E. Feldman H.B. Kalfon L. Raveh-Barak H. Falik-Zaccai T.C. Elpeleg O. Mandel H. ZEE-FEN CHANG |
公開日期: | 2019 | 出版社: | National Academy of Sciences | 卷: | 116 | 期: | 2 | 起(迄)頁: | 566-574 | 來源出版物: | Proceedings of the National Academy of Sciences of the United States of America | 摘要: | We report a patient who presented with congenital hypotonia, hypoventilation, and cerebellar histopathological alterations. Exome analysis revealed a homozygous mutation in the initiation codon of the NME3 gene, which encodes an NDP kinase. The initiation-codon mutation leads to deficiency in NME3 protein expression. NME3 is a mitochondrial outer-membrane protein capable of interacting with MFN1/2, and its depletion causes dysfunction in mitochondrial dynamics. Consistently, the patient’s fibroblasts were characterized by a slow rate of mitochondrial dynamics, which was reversed by expression of wild-type or catalytic-dead NME3. Moreover, glucose starvation caused mitochondrial fragmentation and cell death in the patient’s cells. The expression of wild-type and catalytic-dead but not oligomerization-attenuated NME3 restored mitochondrial elongation. However, only wild-type NME3 sustained ATP production and viability. Thus, the separate functions of NME3 in mitochondrial fusion and NDP kinase cooperate in metabolic adaptation for cell survival in response to glucose starvation. Given the critical role of mitochondrial dynamics and energy requirements in neuronal development, the homozygous mutation in NME3 is linked to a fatal mitochondrial neurodegenerative disorder. ? 2019 National Academy of Sciences. All Rights Reserved. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85059622065&doi=10.1073%2fpnas.1818629116&partnerID=40&md5=ad2862c45234d5dc88339320f9164fab https://scholars.lib.ntu.edu.tw/handle/123456789/454665 |
ISSN: | 0027-8424 | DOI: | 10.1073/pnas.1818629116 | SDG/關鍵字: | adenosine triphosphate; glucose; mitofusin 1; mitofusin 2; nucleoside diphosphate kinase; nucleoside diphosphate kinase 3; nucleoside diphosphate kinase A; unclassified drug; adenosine triphosphate; NME3 protein, human; nucleoside diphosphate kinase NM23; amino terminal sequence; Article; case report; catalysis; cell death; cell elongation; cell fusion; cell survival; cerebellum disease; clinical article; clinical feature; controlled study; degenerative disease; enzyme activity; exome; female; fibroblast; gene function; gene mutation; genetic association; genome analysis; histopathology; human; human cell; human tissue; hypoventilation; infant; male; metabolic regulation; mitochondrial dynamics; muscle hypotonia; nerve cell differentiation; NME3 gene; oligomerization; pedigree; priority journal; protein depletion; protein expression; start codon; starvation; cell line; cell survival; degenerative disease; energy metabolism; enzymology; genetics; homozygote; metabolism; mitochondrion; pathology; Adenosine Triphosphate; Cell Line; Cell Survival; Energy Metabolism; Female; Homozygote; Humans; Male; Mitochondria; Mitochondrial Dynamics; Neurodegenerative Diseases; NM23 Nucleoside Diphosphate Kinases |
顯示於: | 生物化學暨分子生物學科研究所 |
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