NARS2 encodes a mitochondrial asparaginyl-tRNA synthetase that catalyzes attachment of asparagine to its cognate tRNA(Asn) through a two-step ATP-dependent reaction, enabling mitochondrial protein synthesis 1. The enzyme functions as a homodimer, and mutations disrupting dimerization or protein stability impair mitochondrial translation and oxidative phosphorylation capacity 2. Biallelic NARS2 mutations cause a spectrum of mitochondrial disorders linked to oxidative phosphorylation deficiency. Disease severity correlates with mutation type: missense variants cause nonsyndromic deafness (DFNB94) 2, while truncating or compound heterozygous mutations cause severe neurodegenerative phenotypes including Leigh syndrome, infantile-onset epilepsy, developmental delay, and neonatal diabetes (DEND syndrome) [PMID:25807530; 3; 4; 52]. These conditions result from impaired steady-state mt-tRNA(Asn) levels and decreased electron transport chain activity 2. Clinically, NARS2 has emerged as a neonatal diabetes gene 6, with cases responding partially to mitochondrial supportive therapy including vitamin B1, L-carnitine, and coenzyme Q10 4. Notably, NARS2 expression variants associate with Alzheimer's disease risk, suggesting broader neurological relevance 7. Yeast modeling confirms pathogenicity of variants and suggests amino acid supplementation as potential therapy 8.