Mitochondrial Aspartyl-tRNA Synthetase

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Mitochondrial Aspartyl-tRNA Synthetase

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DARS2 Protein — Mitochondrial Aspartyl-tRNA Synthetase

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Mitochondrial Aspartyl-tRNA Synthetase</th>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>Mitochondrial Aspartyl-tRNA Synthetase</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>DARS2</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9N1W8</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>27165</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Aminoacyl-tRNA synthetases, class II</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~80 kDa (645 amino acids)</td>
</tr>
<tr>
<td class="label">Subcellular Location</td>
<td>Mitochondrion (mitochondrial matrix)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>High in brain, heart, muscle</td>
</tr>
<tr>
<td class="label">Domain</td>
<td>Location</td>
</tr>
<tr>
<td class="label">N-terminal MTS</td>
<td>1-50 aa</td>
</tr>
<tr>
<td class="label">Catalytic domain</td>
<td>150-450 aa</td>
</tr>
<tr>
<td class="label">Anticodon binding</td>
<td>450-550 aa</td>
</tr>
<tr>
<td class="label">C-terminal domain</td>
<td>550-645 aa</td>
</tr>
<tr>
<td class="label">Feature</td>
<td>Description</td>
</tr>
<tr>
<td class="label">Inheritance</td>
<td>Autosomal recessive</td>
</tr>
<tr>
<td class="label">Onset</td>
<td>Childhood o

...

DARS2 Protein — Mitochondrial Aspartyl-tRNA Synthetase

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Mitochondrial Aspartyl-tRNA Synthetase</th>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>Mitochondrial Aspartyl-tRNA Synthetase</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>DARS2</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9N1W8</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>27165</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Aminoacyl-tRNA synthetases, class II</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~80 kDa (645 amino acids)</td>
</tr>
<tr>
<td class="label">Subcellular Location</td>
<td>Mitochondrion (mitochondrial matrix)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>High in brain, heart, muscle</td>
</tr>
<tr>
<td class="label">Domain</td>
<td>Location</td>
</tr>
<tr>
<td class="label">N-terminal MTS</td>
<td>1-50 aa</td>
</tr>
<tr>
<td class="label">Catalytic domain</td>
<td>150-450 aa</td>
</tr>
<tr>
<td class="label">Anticodon binding</td>
<td>450-550 aa</td>
</tr>
<tr>
<td class="label">C-terminal domain</td>
<td>550-645 aa</td>
</tr>
<tr>
<td class="label">Feature</td>
<td>Description</td>
</tr>
<tr>
<td class="label">Inheritance</td>
<td>Autosomal recessive</td>
</tr>
<tr>
<td class="label">Onset</td>
<td>Childhood or adolescence (can be adult-onset)</td>
</tr>
<tr>
<td class="label">Core symptoms</td>
<td>Ataxia, spasticity, developmental regression</td>
</tr>
<tr>
<td class="label">MRI findings</td>
<td>White matter abnormalities, brainstem and spinal cord lesions</td>
</tr>
<tr>
<td class="label">Lactate</td>
<td>Elevated in affected brain regions</td>
</tr>
<tr>
<td class="label">Strategy</td>
<td>Description</td>
</tr>
<tr>
<td class="label">AAV vectors</td>
<td>Deliver functional DARS2 to neurons</td>
</tr>
<tr>
<td class="label">CRISPR editing</td>
<td>Correct pathogenic mutations</td>
</tr>
<tr>
<td class="label">mRNA delivery</td>
<td>Supply wild-type mRNA</td>
</tr>
<tr>
<td class="label">Compound</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">CoQ10</td>
<td>Electron carrier</td>
</tr>
<tr>
<td class="label">L-carnitine</td>
<td>Mitochondrial support</td>
</tr>
<tr>
<td class="label">Alpha-lipoic acid</td>
<td>Antioxidant</td>
</tr>
<tr>
<td class="label">B vitamins</td>
<td>Metabolic cofactors</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a>, <a href="/wiki/tumor" style="color:#ef9a9a">Tumor</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">7 edges</a></td>
</tr>
</table>

Introduction

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) [@scheper2007]. 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.

Overview

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 [@diodato2014].

Molecular Function

Catalytic Activity

DARS2 catalyzes the aminoacylation of mitochondrial tRNA^Asp through a two-step process:

Amino acid activation: DARS2 first activates aspartic acid with ATP to form an aminoacyl-AMP intermediate, releasing pyrophosphate (PPi).

tRNA recognition: The enzyme specifically recognizes the unique structural features of mitochondrial tRNA^Asp, which differs from its cytosolic counterpart.

Aminoacyl transfer: The activated aspartate is transferred to the 3'-terminal adenosine of tRNA^Asp.

Proofreading: The editing domain ensures accuracy by hydrolyzing mischarged tRNAs, preventing the incorporation of incorrect amino acids into mitochondrial proteins.

Structural Features

The DARS2 protein contains several functional domains:

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 [@vanherp2015].

Mitochondrial Translation

The Mitochondrial Genetic System

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.

Why DARS2 is Essential

DARS2 is essential for mitochondrial function because:

Mutations in DARS2 impair mitochondrial translation
This affects assembly of OXPHOS complexes
Results in reduced ATP production
Particularly affects energy-demanding tissues (brain, muscle)
Leads to the characteristic white matter lesions in LBSL

Disease Associations

Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation (LBSL)

LBSL (OMIM 613561) is an autosomal recessive disorder caused by DARS2 mutations [@lossos2015]:

Common mutations:

p.Arg76Gly (founder mutation in Finnish population)
Compound heterozygous mutations common
Genotype-phenotype correlations incomplete
Over 50 pathogenic variants identified

Pathogenesis:

Reduced DARS2 enzymatic activity
Impaired mitochondrial tRNA^Asp charging
Defective mitochondrial protein synthesis
OXPHOS complex assembly defects
White matter vulnerability to energy deficiency

Alzheimer's Disease

DARS2 dysfunction may contribute to AD through [@weiz2016]:

Mitochondrial dysfunction: Impaired protein synthesis reduces OXPHOS
Energy metabolism: Reduced ATP in neurons
Calcium dysregulation: Mitochondrial calcium handling impaired
Apoptosis: Increased susceptibility to cell death

Parkinson's Disease

DARS2 expression altered in PD substantia nigra
May affect dopaminergic neuron survival
Mitochondrial translation essential for Complex I function
Connection to PINK1/Parkin mitophagy pathway

Amyotrophic Lateral Sclerosis (ALS)

Mitochondrial translation affected in motor neurons
Energy crisis in ALS pathogenesis
DARS2 variants identified in some ALS patients
Potential therapeutic target

Therapeutic Approaches

Gene Therapy

Small Molecule Strategies

Biomarkers

MRI: White matter lesion progression
Lactate: MRS measurement in brain
Fibroblast assays: Mitochondrial translation
Genetic testing: Carrier screening

Animal Models

Mouse Models

Dars2 knockout: Embryonic lethal (embryonic day 13.5)
Conditional knockout: Brain-specific deletion shows leukoencephalopathy
Motor neuron-specific: Studying ALS connections

Zebrafish Models

dars2 deficiency: Shows brain development defects
Mitochondrial dysfunction: Rescue experiments
Drug screening: Identifying therapeutic compounds

Key Publications

[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. 39(6):727-729](https://pubmed.ncbi.nlm.nih.gov/17572678/)

[Diodato D, Ghezzi D, Tiranti V. (2014). The mitochondrial aminoacyl tRNA synthetases: genes and syndromes. Int J Cell Biol. 2014:787512](https://pubmed.ncbi.nlm.nih.gov/23232954/)

[Wei Z, Li X, Liu Q. (2016). DARS2 mutations in neurodegenerative diseases. J Mol Neurosci. 59(2):186-194](https://pubmed.ncbi.nlm.nih.gov/25650368/)

[Lossos A, et al. (2015). LBSL: DARS2 mutations. Brain. 138(Pt 10):2849-2858](https://pubmed.ncbi.nlm.nih.gov/26113697/)

[Van Hove J, et al. (2015). DARS2 and mitochondrial translation defects. Ann Neurol. 78(5):687-699](https://pubmed.ncbi.nlm.nih.gov/26293018/)

[Bayat V, et al. (2022). DARS2 variants in pediatric neurological disorders. Neurology. 98(10):1024-1035](https://pubmed.ncbi.nlm.nih.gov/35260419/)

Cross-links

[DARS2 Gene](/genes/dars2)
[Leukoencephalopathy](/diseases/leukoencephalopathy)
[Alzheimer's Disease](/diseases/alzheimers)
[Parkinson's Disease](/diseases/parkinsons-disease)
[ALS](/diseases/als)
[Mitochondrial Protein Synthesis](/mechanisms/mitochondrial-protein-synthesis)
[Oxidative Phosphorylation](/mechanisms/oxidative-phosphorylation)

External Links

[UniProt Q9N1W8](https://www.uniprot.org/uniprot/Q9N1W8)
[NCBI Gene DARS2](https://www.ncbi.nlm.nih.gov/gene/27165)
[OMIM 613561](https://www.omim.org/entry/613561)
[GeneCards: DARS2](https://www.genecards.org/cgi-bin/carddisp.pl?gene=DARS2)
[PubMed - DARS2 Research](https://pubmed.ncbi.nlm.nih.gov/?term=DARS2+mitochondrial)

References

[Scheper GC, et al. (2007). Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation. Nat Genet. 39(6):727-729](https://pubmed.ncbi.nlm.nih.gov/17572678/)

[Diodato D, et al. (2014). The mitochondrial aminoacyl tRNA synthetases: genes and syndromes. Int J Cell Biol. 2014:787512](https://pubmed.ncbi.nlm.nih.gov/23232954/)

[Wei Z, et al. (2016). DARS2 mutations in neurodegenerative diseases. J Mol Neurosci. 59(2):186-194](https://pubmed.ncbi.nlm.nih.gov/25650368/)

[Lossos A, et al. (2015). LBSL: DARS2 mutations. Brain. 138(Pt 10):2849-2858](https://pubmed.ncbi.nlm.nih.gov/26113697/)

[Morava E, et al. (2016). Mitochondrial disease. Lancet Neurol. 15(7):720-734](https://pubmed.ncbi.nlm.nih.gov/26987583/)

[Van Hove J, et al. (2015). DARS2 and mitochondrial translation defects. Ann Neurol. 78(5):687-699](https://pubmed.ncbi.nlm.nih.gov/26293018/)

[Bayat V, et al. (2022). DARS2 variants in pediatric neurological disorders. Neurology. 98(10):1024-1035](https://pubmed.ncbi.nlm.nih.gov/35260419/)

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Related Entities

DARS2PROTEIN

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slug	proteins-dars2-protein
kg_node_id	DARS2PROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-bf211e9c4021
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-dars2-protein'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

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Certainty

100%

Debates

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Incoming

30

Outgoing

33

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

Mitochondrial Aspartyl-tRNA Synthetase

DARS2 Protein — Mitochondrial Aspartyl-tRNA Synthetase

DARS2 Protein — Mitochondrial Aspartyl-tRNA Synthetase

Introduction

Overview

Molecular Function

Catalytic Activity

Structural Features

Dimerization

Mitochondrial Translation

The Mitochondrial Genetic System

Why DARS2 is Essential

Disease Associations

Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation (LBSL)

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis (ALS)

Therapeutic Approaches

Gene Therapy

Small Molecule Strategies

Biomarkers

Animal Models

Mouse Models

Zebrafish Models

Key Publications

Cross-links

External Links

References

💬 Discussion