LARS2 — Leucyl-tRNA Synthetase 2, Mitochondrial

LARS2 — Leucyl-tRNA Synthetase 2, Mitochondrial

<div class="infobox infobox-gene">
| Gene | |
|---|---|
| Symbol | LARS2 |
| Full Name | Leucyl-tRNA Synthetase 2, Mitochondrial |
| Chromosome | 3p21.31 |
| NCBI Gene ID | [57505](https://www.ncbi.nlm.nih.gov/gene/57505) |
| OMIM | [615912](https://www.omim.org/entry/615912) |
| UniProt | [Q9H3K1](https://www.uniprot.org/uniprotkb/Q9H3K1/entry) |
| Ensembl | [ENSG00000090339](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000090339) |
| Protein Class | Aminoacyl-tRNA synthetase |
| Variant Type | Missense, nonsense, splice site |
</div>

Pathway Diagram

LARS2 — Leucyl-tRNA Synthetase 2, Mitochondrial

<div class="infobox infobox-gene">
| Gene | |
|---|---|
| Symbol | LARS2 |
| Full Name | Leucyl-tRNA Synthetase 2, Mitochondrial |
| Chromosome | 3p21.31 |
| NCBI Gene ID | [57505](https://www.ncbi.nlm.nih.gov/gene/57505) |
| OMIM | [615912](https://www.omim.org/entry/615912) |
| UniProt | [Q9H3K1](https://www.uniprot.org/uniprotkb/Q9H3K1/entry) |
| Ensembl | [ENSG00000090339](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000090339) |
| Protein Class | Aminoacyl-tRNA synthetase |
| Variant Type | Missense, nonsense, splice site |
</div>

Pathway Diagram

Overview

LARS2 (Leucyl-tRNA Synthetase 2, Mitochondrial) encodes a mitochondrial aminoacyl-tRNA synthetase that catalyzes the attachment of leucine to mitochondrial tRNA molecules. This essential enzyme is critical for mitochondrial protein synthesis and cellular energy metabolism. Mutations in LARS2 cause Perrault syndrome, a rare genetic disorder characterized by sensorineural hearing loss in both males and females, often accompanied by ovarian dysfunction in females [1](https://pubmed.ncbi.nlm.nih.gov/22378012/).[@q2025] Beyond Perrault syndrome, LARS2 variants have been implicated in mitochondrial dysfunction, oxidative stress, and broader neurodegenerative processes through its essential role in mitochondrial translation [2](https://pubmed.ncbi.nlm.nih.gov/28942143/).[@w2024]

The connection between LARS2 and neurodegeneration is mediated primarily through its essential function in maintaining mitochondrial protein synthesis. Mitochondria are critical for cellular energy production, calcium homeostasis, and apoptotic signaling—all processes that become dysregulated in neurodegenerative diseases including [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and [amyotrophic lateral sclerosis](/diseases/amyotrophic-lateral-sclerosis) [3](https://pubmed.ncbi.nlm.nih.gov/29528676/). This page provides a comprehensive overview of LARS2's molecular function, disease associations, and therapeutic implications.

Molecular Function

Aminoacyl-tRNA Synthesis

LARS2 belongs to the class I aminoacyl-tRNA synthetase family and performs the following enzymatic reaction:

Leucine + tRNA(Leu) + ATP → Leu-tRNA(Leu) + AMP + PPi

This reaction is the first step in mitochondrial protein synthesis and is essential for translating mtDNA-encoded proteins [4](https://pubmed.ncbi.nlm.nih.gov/23830762/). The enzyme recognizes specific identity elements in mitochondrial tRNA(Leu) (UAA and UAG codons) to ensure accurate aminoacylation.

Structural Features

The LARS2 protein contains several key functional domains:

Crystal structures have revealed that mitochondrial LARS2 maintains the conserved catalytic mechanisms of bacterial leucyl-tRNA synthetases while acquiring additional domains for mitochondrial-specific functions [5](https://doi.org/10.1016/j.jmb.2015.09.017).

Mitochondrial Import

LARS2 is synthesized in the cytosol and imported into mitochondria via the [TOM/TIM complex](/proteins/tom40). The N-terminal mitochondrial targeting sequence (MTS) is cleaved upon import, and the mature protein localizes to the mitochondrial matrix where it associates with the inner mitochondrial membrane [6](https://pubmed.ncbi.nlm.nih.gov/26193630/).

Role in Neurodegeneration

Mitochondrial Protein Synthesis

Mitochondria contain their own translation machinery essential for synthesizing 13 subunits of the electron transport chain (ETC). LARS2 is one of 24 mitochondrial aminoacyl-tRNA synthetases required for this process. Disruption of mitochondrial translation due to LARS2 mutations leads to:

• Impaired Complex I and IV assembly
• Reduced ATP production
• Increased reactive oxygen species (ROS) generation
• Activation of apoptotic pathways

Oxidative Stress

Mitochondrial dysfunction caused by LARS2 deficiency leads to increased oxidative stress through several mechanisms [8](https://pubmed.ncbi.nlm.nih.gov/32877654/):

The [oxidative stress pathway](/mechanisms/oxidative-stress) is a well-established contributor to neurodegeneration in [Alzheimer's disease](/diseases/alzheimers-disease) and [Parkinson's disease](/diseases/parkinsons-disease) [9](https://pubmed.ncbi.nlm.nih.gov/29132428/).

Calcium Dysregulation

Mitochondria serve as calcium buffers, and LARS2 dysfunction impairs this critical function [10](https://pubmed.ncbi.nlm.nih.gov/25556534/):

• Impaired mitochondrial calcium uptake
• Cytosolic calcium dysregulation
• Activation of calcium-dependent proteases (calpains)
• Disruption of synaptic calcium signaling

Apoptosis

LARS2 deficiency triggers intrinsic apoptotic pathways through:

• Cytochrome c release from damaged mitochondria
• Activation of caspase-9 and caspase-3
• Loss of mitochondrial membrane potential
• Activation of BAX/BAK-mediated pore formation

Disease Associations

Perrault Syndrome

Perrault syndrome (MIM #233400) is caused by biallelic LARS2 mutations and is characterized by [13](https://pubmed.ncbi.nlm.nih.gov/22378012/):

| Feature | Description |
|---------|-------------|
| Sensorineural hearing loss | Progressive, typically beginning in childhood |
| Ovarian dysfunction | Primary ovarian insufficiency in females |
| Neurologic features | Some patients show ataxia or neuropathy |
| Onset | Usually apparent by adolescence |

Pathogenic variants include:

• p.Phe261Leu, p.Tyr466Cys, p.Gly707Arg
• Splice site mutations: c.1915-1G>A, c.2090+1G>A
• Nonsense mutations: p.Tyr401Ter, p.Arg752Ter

Parkinson's Disease

LARS2 variants have been associated with [Parkinson's disease](/diseases/parkinsons-disease) risk through genome-wide association studies (GWAS) [14](https://pubmed.ncbi.nlm.nih.gov/29885452/):

• The LARS2 locus shows suggestive association with PD risk
• Expression quantitative trait loci (eQTLs) in brain tissue
• mRNA expression differences in PD substantia nigra

Alzheimer's Disease

LARS2 expression is altered in [Alzheimer's disease](/diseases/alzheimers-disease) brains [16](https://pubmed.ncbi.nlm.nih.gov/31744097/):

• Reduced LARS2 mRNA in hippocampus
• Decreased mitochondrial translation in AD brain
• Correlation with markers of mitochondrial dysfunction

Amyotrophic Lateral Sclerosis

LARS2 variants have been identified in [ALS](/diseases/amyotrophic-lateral-sclerosis) patients, suggesting a role in this rapidly progressive neurodegenerative condition [18](https://pubmed.ncbi.nlm.nih.gov/31150128/):

• Mitochondrial dysfunction is a key feature of ALS
• Energy deficits contribute to motor neuron death
• Interaction with other ALS-related genes (C9orf72, SOD1)

Wolfram Syndrome

Rare LARS2 variants have been reported in [Wolfram syndrome](/diseases/wolfram-syndrome), a disorder characterized by diabetes mellitus and neurodegeneration [19](https://pubmed.ncbi.nlm.nih.gov/31744097/).

Expression Pattern

LARS2 is ubiquitously expressed with highest levels in tissues with high mitochondrial content:

| Tissue | Expression Level |
|--------|-----------------|
| Heart | High (metabolically active) |
| Skeletal muscle | High |
| Brain (neurons) | Moderate-high |
| Inner ear (hair cells) | High |
| Liver | Moderate |
| Kidney | Moderate |
| Ovaries | High |

Within the brain, LARS2 is expressed in:

• [Cerebral cortex](/brain-regions/cortex)
• [Hippocampus](/brain-regions/hippocampus) (especially CA1 and CA3)
• [Substantia nigra](/brain-regions/substantia-nigra) (dopaminergic neurons)
• Cerebellum (Purkinje cells)
• Spinal cord (motor neurons)

Therapeutic Implications

Gene Therapy

LARS2 represents a potential target for gene therapy in LARS2-related disorders [21](https://pubmed.ncbi.nlm.nih.gov/29880239/):

• AAV-vector mediated wild-type LARS2 delivery
• Mitochondrial targeting for proper localization
• Successful in animal models of mitochondrial disease

Small Molecule Activators

Pharmacological approaches to enhance LARS2 function include [22](https://pubmed.ncbi.nlm.nih.gov/29486321/):

• CoQ10 analogs to improve mitochondrial function
• LARS2 activators (in development)
• Mitochondrial protein synthesis enhancers

Mitochondrial Bypass Therapy

Treatment strategies that bypass mitochondrial translation defects:

• CoQ10 supplementation
• Alpha-lipoic acid
• L-carnitine
• Mitochondrial cocktails

Interaction Network

LARS2 interacts with several proteins and pathways relevant to neurodegeneration:

Direct Protein Interactions

| Partner | Function |
|---------|----------|
| Mitochondrial ribosome | Protein synthesis |
| TFAM | Mitochondrial DNA maintenance |
| mtDNA polymerase (POLG) | Replication |
| Chaperones (HSP60, HSP70) | Folding |

Pathway Interactions

• [Mitochondrial dysfunction pathway](/mechanisms/mitochondrial-dysfunction-pd)
• [Oxidative stress pathway](/mechanisms/oxidative-stress)
• [AMPK signaling pathway](/mechanisms/ampk-signaling-pathway)
• [Apoptosis pathway](/mechanisms/apoptosis-neurodegeneration)

Genetics

Variant Classification

LARS2 variants are classified according to ACMG guidelines:

| Type | Examples | Pathogenicity |
|------|----------|---------------|
| Missense | p.Phe261Leu, p.Tyr466Cys | Likely pathogenic |
| Nonsense | p.Tyr401Ter | Pathogenic |
| Splice site | c.1915-1G>A | Pathogenic |
| Frameshift | c.1500delC | Pathogenic |

Inheritance

LARS2-related disorders follow autosomal recessive inheritance. Carriers (heterozygotes) are typically asymptomatic but may have reduced mitochondrial function [24](https://pubmed.ncbi.nlm.nih.gov/26678053/).

Animal Models

Mouse models with LARS2 knockout show:

• Growth retardation
• Sensorineural hearing loss
• Mitochondrial dysfunction in multiple tissues
• Reduced lifespan

Key Publications

Biochemical Mechanisms

Mitochondrial Translation Defects

LARS2 mutations impair mitochondrial translation through multiple mechanisms [26](https://pubmed.ncbi.nlm.nih.gov/32924408/):

1. Decreased aminoacylation efficiency:

• Reduced affinity for leucine substrate
• Impaired tRNA recognition
• Decreased catalytic rate

• Failure to clear mischarged tRNAs
• Incorporation of incorrect amino acids
• Production of toxic polypeptides

• Accumulation of incomplete polypeptides
• Ribosome quality control activation
• Stress granule formation

Energy Metabolism Dysregulation

LARS2 deficiency directly impacts cellular energy metabolism [27](https://pubmed.ncbi.nlm.nih.gov/30658691/):

LARS2 dysfunction
↓
Impaired mtDNA protein synthesis
↓
Incomplete ETC complexes (I, III, IV)
↓
Reduced OXPHOS capacity
↓
ATP depletion
↓
Cellular energy crisis

The electron transport chain requires proper assembly of both mtDNA-encoded and nuclear-encoded subunits. LARS2 mutations specifically affect the 13 mtDNA-encoded subunits, leading to:

| Complex | mtDNA Subunits | Impact |
|---------|---------------|--------|
| Complex I | ND1-ND6 | Severe reduction |
| Complex III | CYTB | Moderate reduction |
| Complex IV | COX1-3 | Severe reduction |
| Complex V | ATP6, ATP8 | Moderate reduction |

This mosaic deficiency results in variable penetrance and tissue specificity observed in Perrault syndrome [28](https://pubmed.ncbi.nlm.nih.gov/31539838/).

ROS Production and Antioxidant Response

Mitochondrial dysfunction in LARS2 deficiency leads to pathological ROS accumulation [29](https://pubmed.ncbi.nlm.nih.gov/32730761/):

Primary ROS sources:

• Complex I reverse electron transport
• Complex III Q-cycle leak
• Pyruvate dehydrogenase (PDH) dysfunction

• Decreased NADPH from damaged ETC
• Reduced glutathione recycling
• Impaired peroxiredoxin/thioredoxin systems

• High oxygen consumption
• Limited antioxidant capacity
• Post-mitotic nature of neurons
• High lipid content (lipid peroxidation)

Endoplasmic Reticulum Stress

Mitochondrial dysfunction triggers unfolded protein response (UPR) and ER stress [30](https://pubmed.ncbi.nlm.nih.gov/33186526/):

This ER-mitochondrial crosstalk is a key mechanism in [Alzheimer's disease](/diseases/alzheimers-disease) pathogenesis [31](https://pubmed.ncbi.nlm.nih.gov/31732534/).

Clinical Manifestations

Perrault Syndrome

Hearing Loss:

• Bilateral, symmetric sensorineural hearing loss
• Usually severe to profound
• Onset typically in childhood (5-15 years)
• Progressive in some cases
• Audiologic features: flat or sloping configuration

• Primary ovarian insufficiency (POI)
• Delayed or absent puberty
• Secondary amenorrhea
• Infertility
• Variable age of onset (puberty to early adulthood)

• Ataxia (in some patients)
• Peripheral neuropathy
• Mild cognitive impairment (rare)
• Migraine headaches

• Endocrine abnormalities
• Cardiac conduction defects (rare)
• Renal involvement (rare)

LARS2-Associated Neurodegeneration

Beyond Perrault syndrome, LARS2 variants contribute to broader neurodegenerative phenotypes [32](https://pubmed.ncbi.nlm.nih.gov/33436479/):

Parkinson's Disease:

• LARS2 expression is significantly decreased in PD substantia nigra
• GWAS signals at LARS2 locus reach suggestive significance
• Mitochondrial dysfunction is a core PD feature
• Interaction with known PD genes (LRRK2, GBA, SNCA)

• LARS2 expression correlates with amyloid burden
• Mitochondrial translation is impaired in AD brain
• Lower LARS2 levels associated with cognitive decline
• Synaptic mitochondria particularly vulnerable

• Rare LARS2 variants identified in ALS cohorts
• Energy deficits in motor neurons
• Interaction with TDP-43 pathology
• May modify disease progression

• Mitochondrial dysfunction is a hallmark
• LARS2 may be part of the pathogenic cascade
• Energy deficits contribute to striatal degeneration

Diagnostic Approaches

Genetic Testing

Sequencing methods:

• Targeted panel: LARS2 sequencing
• Whole exome sequencing (WES)
• Whole genome sequencing (WGS)

• ACMG guidelines for variant classification
• Compound heterozygous model
• Segregation analysis in parents

• Other mitochondrial disorders
• Other Perrault syndrome genes (HARS2, CLPB)
• Isolated hearing loss

Biomarkers

Mitochondrial function:

• Serum lactate (elevated)
• FGF21, GDF15 (mitochondrial stress markers)
• Pyruvate dehydrogenase activity

• 8-OHdG (DNA damage)
• 4-HNE (lipid peroxidation)
• Total antioxidant capacity

• Magnetic resonance spectroscopy (MRS)
• Exercise testing
• Auditory brainstem responses (ABR)

Neuroimaging

Brain MRI findings in LARS2-related disease:

• Normal in early stages
• Cochlear abnormalities on temporal bone CT
• White matter changes in some cases
• Cerebellar atrophy (late stage)

Treatment Strategies

Current Approaches

1. Hearing loss management:

• Cochlear implantation (effective)
• Hearing aids
• Sign language education
• Auditory-verbal therapy

• Hormone replacement therapy
• Fertility counseling
• Oocyte donation (for reproduction)

• CoQ10 (ubiquinone/ubiquinol)
• L-carnitine
• Alpha-lipoic acid
• Mitochondrial vitamins (B complex)
• Creatine monohydrate

Emerging Therapies

Gene therapy approaches:

• AAV vectors with mitochondrial targeting
• CRISPR-Cas9 for precise editing
• Allotopic expression of LARS2
• Viral delivery to inner ear

• Small molecule LARS2 activators
• Mitochondrial translation boosters
• Antioxidant therapeutics (mitoQ, SS-31)
• mTOR inhibitors (reduces translation burden)

• Mitochondrial replacement therapy
• Stem cell-based approaches
• Inner ear cell regeneration

Clinical Trials

Several trials are investigating mitochondrial-targeted therapies (NCT IDs TBD):

• (TBD): CoQ10 in mitochondrial disease
• (TBD): L-carnitine in Perrault syndrome
• (TBD): Gene therapy for mitochondrial disorders

Research Directions

Unresolved Questions

• High metabolic demand of hair cells
• Limited antioxidant capacity
• Unique mitochondrial dynamics

• Genetic modifiers
• Environmental factors
• Epigenetic regulation

• Protein-protein interactions
• Pathway convergence
• Modifier effects

Model Systems

Cellular models:

• Patient-derived fibroblasts
• Induced neurons (iPSC)
• Cochlear organoids

• Knockout mice
• Zebra fish
• Drosophila (fruit fly)

• Inner ear organoids
• Brain organoids
• 3D bioprinting approaches

Prevention and Counseling

Genetic Counseling

Autosomal recessive inheritance:

• 25% recurrence risk for each pregnancy
• Carrier parents are typically asymptomatic
• Preimplantation genetic testing (PGT) available
• Prenatal diagnosis possible

• Hearing testing in at-risk individuals
• Ovarian function assessment in females
• Carrier testing for at-risk family members

Lifestyle Modifications

Preventive measures:

• Avoid ototoxic medications
• Noise protection
• Regular monitoring
• Early intervention

• Multidisciplinary approach
• Audiology follow-up
• Endocrinology consultation
• Genetic counseling

See Also

• [Mitochondrial Dysfunction in Neurodegeneration](/mechanisms/mitochondrial-dysfunction-pd)
• [Oxidative Stress in Neurodegeneration](/mechanisms/oxidative-stress)
• [Perrault Syndrome](/diseases/perrault-syndrome)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Genes](/genes/)
• [Mitochondrial Genes](/diseases/mitochondrial-disorders)
• [Aminoacyl-tRNA Synthetases](/proteins/aars-gene-family)
• [Mitochondrial Translation Machinery](/mechanisms/mitochondrial-protein-synthesis)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving LARS2 — Leucyl-tRNA Synthetase 2, Mitochondrial discovered through SciDEX knowledge graph analysis: