Two separate functions of NME3 critical for cell survival underlie a neurodegenerative disorder.

Autor:	Chen CW; Institute of Molecular Medicine, College of Medicine, National Taiwan University, 10002 Taipei, Taiwan., Wang HL; Institute of Molecular Medicine, College of Medicine, National Taiwan University, 10002 Taipei, Taiwan., Huang CW; Department of Medicine, College of Medicine, National Taiwan University, 10002 Taipei, Taiwan., Huang CY; Institute of Biochemistry and Molecular Biology, National Yang-Ming University, 11221 Taipei, Taiwan., Lim WK; Institute of Molecular Medicine, College of Medicine, National Taiwan University, 10002 Taipei, Taiwan., Tu IC; Institute of Molecular Medicine, College of Medicine, National Taiwan University, 10002 Taipei, Taiwan., Koorapati A; Institute of Molecular Medicine, College of Medicine, National Taiwan University, 10002 Taipei, Taiwan., Hsieh ST; Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, 10002 Taipei, Taiwan., Kan HW; Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, 10002 Taipei, Taiwan., Tzeng SR; Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, 10002 Taipei, Taiwan., Liao JC; Institute of Atomic and Molecular Sciences, Academia Sinica, 10617 Taipei, Taiwan., Chong WM; Institute of Atomic and Molecular Sciences, Academia Sinica, 10617 Taipei, Taiwan., Naroditzky I; Department of Pathology, Rambam Health Care Campus, 31096 Haifa, Israel., Kidron D; Department of Pathology, Meir Hospital, 44100 Kfar Saba, Israel.; Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel., Eran A; Department of Radiology, Rambam Health Care Campus, 31096 Haifa, Israel., Nijim Y; Pediatric and Neonatal Unit, Nazareth Hospital EMMS, 17639 Nazareth, Israel., Sela E; Pediatric and Neonatal Unit, Nazareth Hospital EMMS, 17639 Nazareth, Israel., Feldman HB; The Genetics Institute, Rambam Health Care Campus, 31096 Haifa, Israel., Kalfon L; Institute of Human Genetics, Galilee Medical Center, 22100 Nahariya, Israel., Raveh-Barak H; Institute of Human Genetics, Galilee Medical Center, 22100 Nahariya, Israel., Falik-Zaccai TC; Institute of Human Genetics, Galilee Medical Center, 22100 Nahariya, Israel.; The Azrieli Faculty of Medicine, Bar Ilan University, 13100 Safed, Israel., Elpeleg O; Department of Genetic and Metabolic Diseases, Hadassah Hebrew University Medical Center, 91120 Jerusalem, Israel., Mandel H; Institute of Human Genetics, Galilee Medical Center, 22100 Nahariya, Israel; h_mandel@rambam.health.gov.il zfchang@ntu.edu.tw.; Metabolic Unit, Technion Faculty of Medicine, Rambam Health Care Campus, 31096 Haifa, Israel., Chang ZF; Institute of Molecular Medicine, College of Medicine, National Taiwan University, 10002 Taipei, Taiwan; h_mandel@rambam.health.gov.il zfchang@ntu.edu.tw.; Center of Precision Medicine, College of Medicine, National Taiwan University, 10002 Taipei, Taiwan.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2019 Jan 08; Vol. 116 (2), pp. 566-574. Date of Electronic Publication: 2018 Dec 26.
DOI:	10.1073/pnas.1818629116
Abstrakt:	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. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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