YARS2 — Tyrosyl-tRNA Synthetase 2, Mitochondrial

YARS2 — Tyrosyl-tRNA Synthetase 2, Mitochondrial

<div class="infobox infobox-gene">
| Gene | |
|---|---|
| Symbol | YARS2 |
| Full Name | Tyrosyl-tRNA Synthetase 2, Mitochondrial |
| Chromosome | 12p11.21 |
| NCBI Gene ID | [51091](https://www.ncbi.nlm.nih.gov/gene/51091) |
| OMIM | [613739](https://www.omim.org/entry/613739) |
| UniProt | [Q9Y2Z4](https://www.uniprot.org/uniprotkb/Q9Y2Z4/entry) |
| Ensembl | [ENSG00000143398](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000143398) |
| Protein Type | Mitochondrial aminoacyl-tRNA synthetase |
| Molecular Weight | ~52 kDa |
| Subcellular Location | Mitochondria |
</div>

Overview

YARS2 — Tyrosyl-tRNA Synthetase 2, Mitochondrial

<div class="infobox infobox-gene">
| Gene | |
|---|---|
| Symbol | YARS2 |
| Full Name | Tyrosyl-tRNA Synthetase 2, Mitochondrial |
| Chromosome | 12p11.21 |
| NCBI Gene ID | [51091](https://www.ncbi.nlm.nih.gov/gene/51091) |
| OMIM | [613739](https://www.omim.org/entry/613739) |
| UniProt | [Q9Y2Z4](https://www.uniprot.org/uniprotkb/Q9Y2Z4/entry) |
| Ensembl | [ENSG00000143398](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000143398) |
| Protein Type | Mitochondrial aminoacyl-tRNA synthetase |
| Molecular Weight | ~52 kDa |
| Subcellular Location | Mitochondria |
</div>

Overview

YARS2 (Tyrosyl-tRNA Synthetase 2, Mitochondrial) encodes a mitochondrial aminoacyl-tRNA synthetase (mtaaRS) that catalyzes the attachment of tyrosine to its cognate mitochondrial tRNA during mitochondrial translation. This enzyme is essential for the proper synthesis of mitochondrial-encoded proteins, which are critical components of the oxidative phosphorylation (OXPHOS) system. Mutations in YARS2 cause Myopathy, Lactic Acidosis, and Sideroblastic Anemia (MLASA) syndrome, a rare autosomal recessive mitochondrial disorder characterized by exercise intolerance, muscle weakness, and sideroblastic anemia[@mlasa2019]. Beyond its role in MLASA, emerging evidence suggests that YARS2 and other mitochondrial aminoacyl-tRNA synthetases may contribute to the pathogenesis of common neurodegenerative diseases including Alzheimer's disease and Parkinson's disease through their effects on mitochondrial protein synthesis and cellular energy metabolism[@mitochondrialtranslation2021].

Mitochondrial dysfunction is a hallmark of neurodegeneration, with defects in mitochondrial translation increasingly recognized as important contributors to disease progression. YARS2, as a key component of the mitochondrial translation machinery, represents a potential link between mitochondrial dysfunction and neurodegenerative processes.

Gene Structure and Evolution

The YARS2 gene is located on chromosome 12p11.21 and spans approximately 12 kilobases. The gene consists of 13 exons that encode a 495-amino acid protein. The genomic structure is relatively conserved among mammalian species, with the coding sequence distributed across multiple exons.

Evolutionary Conservation

YARS2 belongs to the class II aminoacyl-tRNA synthetase family and shows high evolutionary conservation:

• Bacterial orthologs: YARS2 shares significant homology with bacterial TyrRS enzymes
• Eukaryotic specialization: YARS2 acquired a mitochondrial targeting sequence (MTS) during evolution
• Domain architecture: The catalytic domain and anticodon-binding domain are highly conserved

Splice Variants

Multiple splice variants of YARS2 have been identified, though their functional significance varies. Some variants may produce proteins with altered subcellular localization or stability.

Protein Structure and Function

YARS2 is a monomeric mitochondrial enzyme that performs the following functions:

Catalytic Activity

YARS2 catalyzes a two-step aminoacylation reaction:

This reaction requires:

• Tyrosine substrate
• ATP
• Magnesium ions
• Mitochondrial tRNA^Tyr (encoded by the mitochondrial genome)

Structural Domains

YARS2 contains several important structural features:

• N-terminal mitochondrial targeting sequence (MTS): Cleaved after import
• Catalytic domain: Binds tyrosine, ATP, and tRNA
• Anticodon-binding domain: Recognizes the tRNA anticodon (GUA)
• C-terminal domain: May participate in protein-protein interactions

Quality Control

YARS2, like other mtaaRSs, has quality control mechanisms:

• Proofreading activity to prevent mischarging
• Interaction with mitochondrial ribosomes
• Potential for degradation of misfolded or damaged protein

Role in Mitochondrial Translation

Mitochondrial translation is essential for producing the 13 oxidative phosphorylation (OXPHOS) complex subunits encoded by mitochondrial DNA. YARS2 plays a critical role in this process:

tRNA Charging

• YARS2 charges mitochondrial tRNA^Tyr with tyrosine
• Proper charging is essential for accurate translation
• Errors in charging can cause ribosomal stalling or mistranslation

Translation Fidelity

• YARS2 proofreading prevents misincorporation of tyrosine
• Mistranslation can produce defective OXPHOS proteins
• Quality control affects overall mitochondrial function

OXPHOS Assembly

Proper mitochondrial translation produces:

• Complex I (NADH dehydrogenase) subunits
• Complex III (cytochrome bc1) subunits
• Complex IV (cytochrome c oxidase) subunits
• Complex V (ATP synthase) subunits

Disease Associations

Myopathy, Lactic Acidosis, and Sideroblastic Anemia (MLASA)

MLASA is a rare autosomal recessive mitochondrial disorder caused by YARS2 mutations[@mlasa2019][@ch2018]:

Clinical Features

• Exercise intolerance: Fatigue and weakness upon exertion
• Myopathy: Progressive muscle weakness, often beginning in childhood
• Lactic acidosis: Elevated lactate in blood, particularly after exercise
• Sideroblastic anemia: Ringed sideroblasts in bone marrow
• Neurological features: Some patients develop ataxia or cognitive impairment

Genetics

• Autosomal recessive inheritance
• Multiple pathogenic variants identified
• Compound heterozygosity common
• Founder mutations in certain populations

Pathogenesis

• Impaired mitochondrial translation
• Reduced OXPHOS capacity
• Accumulation of defective mitochondria
• Tissue-specific vulnerability (muscle, blood-forming cells)

Treatment

• Supportive care
• Exercise management
• Coenzyme Q10 supplementation (variable response)
• Avoidance of metformin (increases lactic acidosis)
• Rarely, ketogenic diet has been attempted

Alzheimer's Disease

Emerging evidence links YARS2 dysfunction to Alzheimer's disease pathogenesis[@yuan2021][@sophos2020]:

Mitochondrial Dysfunction in AD

• Mitochondrial defects are early events in AD
• YARS2 expression altered in AD brain
• May contribute to OXPHOS deficits

Mitochondrial Translation

• Global mitochondrial translation may be impaired
• YARS2 downregulation could contribute to deficits
• Some studies show therapeutic benefit of mitochondrial support

Therapeutic Implications

• Enhancing mitochondrial translation could be beneficial
• YARS2 expression modulation may be therapeutic target

Parkinson's Disease

YARS2 may also be relevant to Parkinson's disease[@su2022]:

Mitochondrial Function

• PD involves mitochondrial defects in dopaminergic neurons
• YARS2 is important for mitochondrial protein synthesis
• YARS2 polymorphisms may influence PD risk

Energy Metabolism

• Dopaminergic neurons have high energy demands
• Impaired OXPHOS increases vulnerability
• YARS2 dysfunction could exacerbate energy deficits

Amyotrophic Lateral Sclerosis (ALS)

YARS2 and mitochondrial translation have been implicated in ALS[@jiang2023]:

Mitochondrial Defects

• Mitochondrial dysfunction is a feature of ALS
• Some patients have YARS2 variants
• May contribute to motor neuron degeneration

Other Disorders

• MELAS syndrome: Related mitochondrial translation defects
• MERRF: Another mitochondrial translation disorder
• Leigh syndrome: Severe childhood encephalopathy

Expression Pattern

YARS2 exhibits tissue-specific expression:

| Tissue | Expression Level |
|--------|-----------------|
| Skeletal muscle | Highest |
| Heart | High |
| Brain | Moderate |
| Liver | Moderate |
| Kidney | Lower |

Brain Distribution

In the brain, YARS2 is expressed in:

• Neurons (especially high-energy-demand neurons)
• [Astrocytes](/cell-types/astrocytes) Oligodendrocytes

Cellular Functions

Energy Production

YARS2 supports OXPHOS through mitochondrial translation:

• Synthesis of 13 mtDNA-encoded proteins
• Assembly of functional OXPHOS complexes
• ATP production via oxidative phosphorylation

Reactive Oxygen Species (ROS)

Mitochondrial function affects ROS production:

• Proper OXPHOS limits electron leak
• Defects increase superoxide production
• YARS2 dysfunction may increase oxidative stress

Calcium Handling

Mitochondria buffer cytosolic calcium:

• Calcium uptake during signaling
• Energy required for calcium pumps
• YARS2 may affect calcium homeostasis

Apoptosis Regulation

Mitochondria are central to apoptosis:

• Cytochrome c release initiates apoptosis
• YARS2 dysfunction may sensitize to apoptosis
• Important in neurodegeneration

Therapeutic Strategies

Small Molecule Approaches

• Coenzyme Q10: Electron carrier supplementation
• L-carnitine: Supports fatty acid metabolism
• Alpha-lipoic acid: Antioxidant and mitochondrial support
• Mitochondrial-targeted antioxidants: MitoQ, MitoVitE

Gene Therapy Approaches

• YARS2 expression: Viral vector delivery
• tRNA modification: Enhance mitochondrial tRNA function
• Mitochondrial translation modulators: Increase translation fidelity

Combination Therapies

• Exercise therapy with mitochondrial support
• Ketogenic diet (may improve mitochondrial function)
• Antioxidant cocktails

Research Models

Cell Culture

• Patient-derived fibroblasts: MLASA patient cells
• iPSC-derived neurons: Disease modeling
• Knockdown/overexpression: Functional studies

Animal Models

• YARS2 knockout mice: Lethal, embryonic/early postnatal
• Conditional knockout: Tissue-specific deletion
• Zebrafish models: Developmental studies

Biochemical Studies

• Enzyme kinetics: Characterization of mutant YARS2
• Structural studies: X-ray crystallography, cryo-EM
• Proteomics: Interaction networks

Summary

YARS2 is an essential mitochondrial aminoacyl-tRNA synthetase that charges mitochondrial tRNA^Tyr with tyrosine, enabling proper mitochondrial translation. Mutations in YARS2 cause MLASA syndrome, a mitochondrial disorder with myopathy, lactic acidosis, and sideroblastic anemia. Beyond this rare disease, YARS2 dysfunction may contribute to common neurodegenerative diseases through its effects on mitochondrial protein synthesis and oxidative phosphorylation. The growing understanding of YARS2's role in mitochondrial function suggests that targeting this enzyme and related mitochondrial translation pathways may have therapeutic potential for Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions.

See Also

• [Mitochondrial Translation](/mechanisms/mitochondrial-translation)
• [Oxidative Phosphorylation](/mechanisms/oxidative-stress-neurodegeneration)
• [Mitochondrial Dysfunction in AD](/mechanisms/mitochondrial-dysfunction-alzheimers)
• [MLASA Syndrome](/diseases/mlasa)
• [Aminoacyl-tRNA Synthetases](/mechanisms/aminoacyl-trna-synthetases)
• [OXPHOS Complexes](/mechanisms/oxphos-complexes)

Brain Atlas Resources

• [Allen Human Brain Atlas - YARS2](https://human.brain-map.org/microarray/search/show?search_term=YARS2)
• [Allen Cell Type Atlas](https://celltypes.brain-map.org/)
• [BrainSpan Atlas of the Developing Human Brain](https://brainspan.org/)
• [Allen Mouse Brain Atlas](https://mouse.brain-map.org/)

References