Mitochondrial Aspartyl Trna Synthetase is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
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).
| 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 |
| Subcellular Location | Mitochondrion (mitochondrial matrix) |
| Expression | High in brain, heart, muscle |
DARS2 is one of the nuclear-encoded mitochondrial aminoacyl-tRNA synthetases (mtaaRSs) that are essential for translating proteins encoded by the mitochondrial genome. These enzymes are responsible for charging mitochondrial tRNAs with their cognate amino acids, a critical step in mitochondrial protein synthesis. Without functional DARS2, mitochondria cannot properly synthesize the 13 essential oxidative phosphorylation (OXPHOS) subunits encoded by mtDNA.
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.
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.
LBSL (OMIM 613561) is an autosomal recessive disorder caused by DARS2 mutations:
| 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:
DARS2 dysfunction may contribute to AD through:
| 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 |
The study of Mitochondrial Aspartyl Trna Synthetase has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
[1] Scheper GC, van der Klok T, van Andel RJ, et al. (2007). Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation. Nat Genet. PMID:17572678
[2] Diodato D, Ghezzi D, Tiranti V. (2014). The mitochondrial aminoacyl tRNA synthetases: genes and syndromes. Int J Cell Biol. PMID:23232954
[3] Wei Z, Li X, Liu Q. (2016). DARS2 mutations in neurodegenerative diseases. J Mol Neurosci. PMID:25650368
[4] Lossos A, et al. (2015). DARS2 mutations in leukoencephalopathy. Brain. PMID:26113697