Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Chen CW

PROVIDER: S-EPMC6329951 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Chen Chih-Wei CW Wang Hong-Ling HL Huang Ching-Wen CW Huang Chang-Yu CY Lim Wai Keong WK Tu I-Chen IC Koorapati Atmaja A Hsieh Sung-Tsang ST Kan Hung-Wei HW Tzeng Shiou-Ru SR Liao Jung-Chi JC Chong Weng Man WM Naroditzky Inna I Kidron Dvora D Eran Ayelet A Nijim Yousif Y Sela Ella E Feldman Hagit Baris HB Kalfon Limor L Raveh-Barak Hadas H Falik-Zaccai Tzipora C TC Elpeleg Orly O Mandel Hanna H Chang Zee-Fen ZF

Proceedings of the National Academy of Sciences of the United States of America 20181226 2

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 <i>NME3</i> 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 ...[more]

PMID: 30587587

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

Publications

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

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