LARS2 (leucyl-tRNA synthetase 2, mitochondrial) catalyzes the aminoacylation of mitochondrial leucyl-tRNA, a critical step in mitochondrial protein translation 1. This enzyme localizes to the mitochondrial matrix and facilitates the attachment of leucine to its cognate tRNA, supporting oxidative phosphorylation and mitochondrial metabolic function 2. Mechanistically, LARS2 maintains mitochondrial translation fidelity and energy metabolism. Disruption of LARS2 function impairs mt-tRNALeu aminoacylation, leading to defective mitochondrial protein synthesis and altered cristae organization 1. LARS2 activity is substrate-dependent, requiring leucine availability, and its expression is upregulated by YAP mechanotransduction in response to matrix stiffness 2. Clinically, LARS2 mutations cause Perrault syndrome, characterized by sensorineural hearing loss and gonadal dysgenesis 3. Beyond genetic disease, LARS2 dysfunction associates with neurodegeneration; reduced LARS2 expression impairs the PI3K-AKT pathway, leading to excessive tau phosphorylation and cognitive decline in Alzheimer's disease models 4. Additionally, LARS2-expressing immunoregulatory B cells promote colorectal cancer immunoevasion through NAD+-dependent metabolic reprogramming, suggesting LARS2 inhibition as a therapeutic strategy 5. LARS2 represents a multifunctional target linking mitochondrial translation, metabolic diseases, neurodegeneration, and cancer immunology.