Aspartyl-tRNA synthetase 2, mitochondrial (DARS2) (DARS2)

Aspartyl-tRNA synthetase 2, mitochondrial (DARS2) is a nuclear-encoded enzyme essential for mitochondrial protein synthesis. It catalyzes the aminoacylation of mitochondrial tRNA-Asp, a critical step for the translation of the 13 essential subunits of the oxidative phosphorylation (OXPHOS) system [UniProt: Q6PI48]. Mutations in the DARS2 gene are primarily associated with Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL), a progressive neurological disorder characterized by white matter abnormalities [PubMed: 17384640]. In addition to its role in rare genetic diseases, DARS2 is frequently overexpressed in various malignancies, including lung and liver cancers, where it promotes tumor cell proliferation and survival by maintaining mitochondrial proteostasis [PubMed: 28611201]. While there are currently no FDA-approved drugs targeting DARS2, it is being investigated as a potential metabolic vulnerability in cancer and as a candidate for gene therapy in LBSL patients [PubMed: 30293983]. Therapeutic strategies focusing on DARS2 must carefully balance the inhibition of tumor growth with the risk of inducing mitochondrial toxicity in healthy tissues.

Other names

Aspartate--tRNA ligase, mitochondrialMT-ASPRSAspartyl-tRNA synthetase 2LBSL

DARS2 catalyzes the two-step reaction of attaching L-aspartate to mitochondrial tRNA(Asp), involving the activation of aspartate with ATP to form an aspartyl-adenylate intermediate followed by the transfer of the aspartyl group to the tRNA [UniProt: Q6PI48].