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.
|Number of pages||9|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - 8 Jan 2019|
Bibliographical noteFunding Information:
ACKNOWLEDGMENTS. We thank the National RNAi Core Facility, Academia Sinica for their help in providing shRNA plasmids and Tet-on plasmids. We thank the staff of the imaging core at the First Core Labs, National Taiwan University College of Medicine for technical assistance. This research is supported by grants from the Ministry of Science and Technology, Taiwan (MOST 107-3017-F-002-002 and MOST 107-2321-B-002-041).
© 2019 National Academy of Sciences. All Rights Reserved.
- Metabolic adaptation
- Mitochondrial fusion
- NDP kinase