NME3 is a mitochondrial outer membrane nucleoside diphosphate kinase that catalyzes phosphoryl transfer from ATP to nucleoside diphosphates via a phosphohistidine intermediate, contributing to nucleoside triphosphate homeostasis 1. Beyond its kinase function, NME3 executes two critical non-catalytic roles: it mediates mitochondrial tethering and fusion through direct phosphatidic acid binding and hexamerization 2, and it facilitates DNA repair of single- and double-stranded breaks by recruiting the ribonucleotide reductase complex to damage sites via interaction with histone acetyltransferase KAT5 3. Recent studies reveal NME3's essential gatekeeping role in hypoxia-induced mitophagy, where its active-site phosphohistidine stabilizes DRP1 against ubiquitination to enable mitochondrial segregation 4. Under mitochondrial redox stress, NME3 recruits to the outer membrane to regulate selective mitophagy and prevent accumulation of dysfunctional mitochondria 5. NME3 deficiency causes severe neurodegeneration, demonstrated by a patient with homozygous initiation-codon mutation presenting congenital hypotonia, cerebellar pathology, and impaired metabolic adaptation to glucose starvation 1. Additionally, NME3 enhances TLR5-mediated NFκB signaling, with expression levels correlating with improved survival in multiple cancer types 6.