YARS2 encodes mitochondrial tyrosyl-tRNA synthetase, which catalyzes the attachment of tyrosine to mitochondrial tRNA(Tyr) in a two-step reaction involving tyrosine activation and transfer to the tRNA acceptor end 1. This enzyme is essential for mitochondrial protein synthesis, as it maintains steady-state levels of aminoacylated tRNA(Tyr) required for translation of respiratory chain subunits 2. Mechanism: YARS2 directly stabilizes oxidative phosphorylation (OXPHOS) complexes through posttranslational interactions with complex I and IV subunits, independent of its primary aminoacylation function 2. Pathogenic mutations reduce catalytic efficiency and aminoacylation activity, leading to impaired mitochondrial protein synthesis and respiratory chain dysfunction 1. Disease Relevance: YARS2 mutations cause Myopathy, Lactic Acidosis, and Sideroblastic Anemia (MLASA), characterized by elevated blood lactate, myopathy, and sideroblastic anemia in 71-88% of patients 3. Mutations also associate with Leber's hereditary optic neuropathy and essential hypertension through mitochondrial dysfunction 45. YARS2 upregulation promotes colorectal cancer progression 6. Clinical Significance: YARS2 mutations demonstrate phenotypic variability ranging from mild to lethal, influenced by mtDNA haplogroup background 7. Prominent complications include hypertrophic cardiomyopathy (53%) and respiratory insufficiency (47%), requiring early surveillance and intervention 3.