Valine--tRNA ligase, mitochondrial

Summary: Valine–tRNA Ligase, Mitochondrial (VARS2)

VARS2 encodes a mitochondrial aminoacyl-tRNA synthetase that catalyzes the attachment of valine to tRNA(Val) in a two-step reaction, forming the aminoacyl-tRNA required for mitochondrial protein synthesis (UniProt: Q5ST30). This 118 kDa enzyme is essential for translational fidelity in the mitochondrial matrix and is part of the broader pathway of mitochondrial oxidative phosphorylation.

Mutations in VARS2 cause Combined Oxidative Phosphorylation Deficiency 20 (COXPD20), a mitochondrial disorder characterized by respiratory chain dysfunction, muscle weakness, progressive external ophthalmoplegia, ataxia, developmental delay, and variable cardiac and neurological manifestations (UniProt: Q5ST30). The disease underscores the critical role of mitochondrial translation in cellular energy metabolism.

In Alzheimer's disease, VARS2 is significantly downregulated in post-mortem AD brain tissue (mean log2 fold-change: −0.40) relative to age-matched controls, as detected by quantitative proteomics (Chaparral AD proteomics). This downregulation may reflect impaired mitochondrial protein synthesis capacity in AD, potentially contributing to the mitochondrial dysfunction observed in neurodegeneration.