TARS2 encodes mitochondrial threonyl-tRNA synthetase, which catalyzes the two-step aminoacylation of threonine to mitochondrial tRNA(Thr) and edits incorrectly charged tRNAs via its editing domain 1. Beyond its canonical role in mitochondrial translation, TARS2 regulates mTORC1 signaling through interaction with inactive Rag GTPases, particularly GTP-RagC, enabling threonine-dependent mTORC1 activation—a function distinct from cytoplasmic threonyl-tRNA synthetase 2. Biallelic pathogenic TARS2 variants cause combined oxidative phosphorylation deficiency 21 (COXPD21), a rare mitochondrial encephalomyopathy presenting with early-onset severe axial hypotonia, limb hypertonia, developmental delay, intractable epilepsy, dystonia, cerebellar atrophy, basal ganglia alterations, and elevated serum lactate 345. Clinical features expand to include hearing impairment, refractory hypokalemia, and hyperhidrosis 65. In vitro studies demonstrate that variants in the TARS2301-381 region impair Rag GTPase binding, dysregulating mTORC1signaling 4. The c.470C>G variant (p.Thr157Arg) represents a Chinese-specific founder mutation 7. Functional rescue studies confirm pathogenicity through restoration of mitochondrial respiration 1, establishing TARS2 as critical for both mitochondrial protein synthesis and nutrient-sensing pathways.