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

Chih Wei Chen, Hong Ling Wang, Ching Wen Huang, Chang Yu Huang, Wai Keong Lim, I. Chen Tu, Atmaja Koorapati, Sung Tsang Hsieh, Hung Wei Kan, Shiou Ru Tzeng, Jung Chi Liao, Weng Man Chong, Inna Naroditzky, Dvora Kidron, Ayelet Eran, Yousif Nijim, Ella Sela, Hagit Baris Feldman, Limor Kalfon, Hadas Raveh-BarakTzipora C. Falik-Zaccai, Orly Elpeleg, Hanna Mandel*, Zee Fen Chang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)566-574
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number2
DOIs
StatePublished - 8 Jan 2019

Keywords

  • Metabolic adaptation
  • Mitochondrial fusion
  • NDP kinase
  • NME3
  • Neurodegeneration

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