The critical function of NME3 in mitochondrial dynamics and adaptation to glucose starvation revealed by a neonatal defect carrying homozygous mutation Zee-Fen Chang1*, Chih-Wei Chen1, Hong-Ling Wang1, Ching-Wen Huang2, Tsang Sung Hsieh2, Jung-Chi Liao3, Orly Elpeleg4, and Hanna Mande5 1Institute of Molecular Medicine, College of Medicine, 2Department of Medicine, College of Medicine, National Taiwan University;3Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, Taiwan; 4Department of Genetic and Metabolic Diseases, Hadassah Hebrew University Medical Center, Jerusalem,5Biochemical Genetics, Technion Faculty of Medicine, Haifa, Israel We report an infant with homozygous mutation in the initiation codon of NME3 gene, which encodes one of NDP kinase isoforms. This infant was born with neurological defects and deceased at 3 months. Our mechanistic investigation demonstrated that NME3 interacts with mitofusins, Mfn1/Mfn2, and promotes the dimerization of mitofusins. NME3 knockdown in normal fibroblasts reduced mitochondrial fusion activity. Consistently, the patient fibroblasts exhibited deficiency in mitochondrial dynamics, aberrant cristae and higher mitochondrial oxidative stress, all of which were reversed by NME3 expression. After glucose deprivation, patient fibroblasts had a significant increase in fragmented mitochondria and cell death due to mitochondrial oxidative stress. Expression of wild-type or catalytic-dead NME3 restored mitochondrial elongation, but only wild-type NME3 reduced glucose starvation-induced oxidative stress and sustained cell viability. Thus, NME3 is critical for mitochondrial fusion independent of the catalytic activity, but in glucose deprivation its catalytic function becomes essential for survival. This investigation suggests the importance of NME3 in mitochondrial dynamics and adaptation to metabolic stress, which deficiencies might contribute to neurological defect developed in the patient.
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