Institute of Molecular Medicine, College of Medicine, National Taiwan University, 10002 Taipei, Taiwan.
Department of Medicine, College of Medicine, National Taiwan University, 10002 Taipei, Taiwan.
Proc Natl Acad Sci U S A. 2019 Jan 8;116(2):566-574. doi: 10.1073/pnas.1818629116. Epub 2018 Dec 26.
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 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 is linked to a fatal mitochondrial neurodegenerative disorder.
我们报告了一例先天气虚、低通气和小脑组织病理学改变的患者。外显子组分析显示，该基因的起始密码子发生纯合突变，该基因编码 NDP 激酶。起始密码子突变导致 NME3 蛋白表达缺陷。NME3 是一种线粒体外膜蛋白，能够与 MFN1/2 相互作用，其耗竭导致线粒体动力学功能障碍。一致地，患者的成纤维细胞表现出线粒体动力学缓慢的特征，这一特征通过表达野生型或催化失活的 NME3 得到逆转。此外，葡萄糖饥饿导致患者细胞中线粒体碎片化和细胞死亡。野生型和催化失活但不是寡聚化减弱的 NME3 的表达恢复了线粒体的伸长。然而，只有野生型 NME3 维持了 ATP 的产生和活力。因此，NME3 在线粒体融合和 NDP 激酶中的独立功能在代谢适应中协同作用，以响应葡萄糖饥饿来维持细胞存活。鉴于线粒体动力学和能量需求在神经元发育中的关键作用， 中的纯合突变与致命的线粒体神经退行性疾病有关。
