DARS2 (Mitochondrial Aspartyl-tRNA Synthetase) is an essential enzyme that catalyzes the attachment of aspartic acid to its cognate tRNA in mitochondria. This enzyme is crucial for mitochondrial protein synthesis and is mutated in patients with a severe neurological disorder called Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation (LBSL) [1]. DARS2 is one of the nuclear-encoded mitochondrial aminoacyl-tRNA synthetases (mtaaRSs) that are essential for translating proteins encoded by the mitochondrial genome. Without functional DARS2, mitochondria cannot properly synthesize the 13 essential oxidative phosphorylation (OXPHOS) subunits encoded by mtDNA, leading to devastating neurological consequences.
| Property | Value |
|---|---|
| Protein Name | Mitochondrial Aspartyl-tRNA Synthetase |
| Gene Symbol | DARS2 |
| UniProt ID | Q9N1W8 |
| NCBI Gene ID | 27165 |
| Protein Family | Aminoacyl-tRNA synthetases, class II |
| Molecular Weight | ~80 kDa (645 amino acids) |
| Subcellular Location | Mitochondrion (mitochondrial matrix) |
| Expression | High in brain, heart, muscle |
DARS2 is expressed predominantly in tissues with high mitochondrial energy demands, including the brain, heart, and skeletal muscle. The enzyme is nuclear-encoded but functions within mitochondria, where it charges mitochondrial tRNA^Asp with aspartic acid. This aminoacylation is a critical step in mitochondrial translation, enabling the synthesis of the 13 proteins encoded by mtDNA [2].
DARS2 catalyzes the aminoacylation of mitochondrial tRNA^Asp through a two-step process:
The DARS2 protein contains several functional domains:
| Domain | Location | Function |
|---|---|---|
| N-terminal MTS | 1-50 aa | Mitochondrial targeting sequence |
| Catalytic domain | 150-450 aa | Aminoacyl-AMP formation |
| Anticodon binding | 450-550 aa | tRNA^Asp recognition |
| C-terminal domain | 550-645 aa | Dimerization |
DARS2 functions as a homodimer, with dimerization essential for enzymatic activity. The dimer interface is formed by the C-terminal domains, and mutations affecting dimerization cause LBSL. Each monomer contributes to the formation of a functional catalytic center, with the two active sites working cooperatively [3].
Mitochondria encode 13 proteins essential for oxidative phosphorylation (Complex I, III, IV, V, and pyruvate dehydrogenase). All 13 mitochondrial-encoded proteins require mitochondrial tRNAs for their translation. The mitochondrial genetic system is distinct from the cytosolic system, with its own tRNAs, rRNAs, and aminoacyl-tRNA synthetases.
DARS2 is essential for mitochondrial function because:
LBSL (OMIM 613561) is an autosomal recessive disorder caused by DARS2 mutations [4]:
| Feature | Description |
|---|---|
| Inheritance | Autosomal recessive |
| Onset | Childhood or adolescence (can be adult-onset) |
| Core symptoms | Ataxia, spasticity, developmental regression |
| MRI findings | White matter abnormalities, brainstem and spinal cord lesions |
| Lactate | Elevated in affected brain regions |
Common mutations:
Pathogenesis:
DARS2 dysfunction may contribute to AD through [5]:
| Strategy | Description | Status |
|---|---|---|
| AAV vectors | Deliver functional DARS2 to neurons | Preclinical |
| CRISPR editing | Correct pathogenic mutations | Research |
| mRNA delivery | Supply wild-type mRNA | Experimental |
| Compound | Mechanism | Status |
|---|---|---|
| CoQ10 | Electron carrier | Investigational |
| L-carnitine | Mitochondrial support | Investigational |
| Alpha-lipoic acid | Antioxidant | Research |
| B vitamins | Metabolic cofactors | Supportive care |
Scheper GC, et al. Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy. Nat Genet. 2007. ↩︎
Diodato D, et al. The mitochondrial aminoacyl tRNA synthetases genes and syndromes. Int J Cell Biol. 2014. ↩︎
Van Hove J, et al. DARS2 and mitochondrial translation defects. Ann Neurol. 2015. ↩︎
Lossos A, et al. LBSL DARS2 mutations. Brain. 2015. ↩︎
Wei Z, et al. DARS2 mutations in neurodegenerative diseases. J Mol Neurosci. 2016. ↩︎