TXN2 — Thioredoxin 2

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TXN2 — Thioredoxin 2

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2">TXN2</th></tr>
<tr><td>Full Name</td><td>Thioredoxin 2</td></tr>
<tr><td>Location</td><td>Chr 22q12.3</td></tr>
<tr><td>NCBI Gene ID</td><td><a href="https://www.ncbi.nlm.nih.gov/gene/25828" target="_blank">25828</a></td></tr>
<tr><td>OMIM</td><td><a href="https://www.omim.org/entry/609063" target="_blank">609063</a></td></tr>
<tr><td>Ensembl</td><td><a href="https://www.ensembl.org/Homo_sapiens/Gene/View?g=ENSG00000100367" target="_blank">ENSG00000100367</a></td></tr>
<tr><td>UniProt</td><td><a href="https://www.uniprot.org/uniprot/Q99757" target="_blank">Q99757</a></td></tr>
<tr><td>Associated Diseases</td><td>Hyperglycinemia, Mitochondrial disorders, Neurodegeneration</td></tr>
</table>
</div>

Overview

[TXN2](/genes/txn2) (Thioredoxin 2) is a mitochondrial member of the thioredoxin family of oxidoreductases that plays a central role in maintaining cellular redox homeostasis[@holmgren1989]. As the primary mitochondrial thioredoxin, TXN2 provides reducing equivalents for peroxiredoxins, regulates mitochondrial redox signaling, and protects against oxidative damage in [neurons](/entities/neurons)[@lu2014].

Gene and Protein Structure

The TXN2 gene is located on chromosome 22q12.3 and spans approximately 8 kb. Key features include:

...

TXN2 — Thioredoxin 2

Overview

Gene and Protein Structure

The TXN2 gene is located on chromosome 22q12.3 and spans approximately 8 kb. Key features include:

N-terminal mitochondrial targeting sequence: 60 amino acid presequence for mitochondrial import
Thioredoxin domain: Contains the canonical CXXC active site motif (CGPC)
Catalytic cysteines: Cys93 and Cys96 for disulfide/dithiol exchange

TXN2 is processed upon mitochondrial import from a 166 amino acid precursor to a 108 amino acid mature protein[@spyrou1997].

Function

Redox Regulation

TXN2 serves as a key electron donor in mitochondrial redox reactions:

Peroxiredoxin reduction: Regenerates reduced [PRDX3](/genes/prdx3) after peroxide reduction
Protein disulfide reduction: Reduces oxidized mitochondrial proteins
Redox signaling: Controls local H₂O₂ concentrations and redox-sensitive signaling[@arnr2000]

Mitochondrial Thioredoxin System

TXN2 is a core component of the mitochondrial thioredoxin system:

TXN2: Primary electron donor
TXN2/thioredoxin reductase 2 (TXNRD2): Regenerates reduced TXN2 using NADPH
PRDX3: Primary TXN2 substrate for H₂O₂ reduction[@zhang2017]

Apoptosis Regulation

TXN2 modulates the intrinsic [apoptosis](/entities/apoptosis) pathway:

Inhibits cytochrome c release from mitochondria
Interacts with apoptosis signal-regulating kinase 1 (ASK1)
Regulates mitochondrial membrane potential
Suppresses caspase activation[@zhang2004]

Mitochondrial DNA Protection

TXN2 protects mitochondrial genome integrity:

Reduces oxidized nucleotides in mtDNA
Supports DNA repair enzyme activity
Prevents oxidative damage-induced mtDNA mutations[@yoshida2019]

Disease Associations

Primary Mitochondrial Disorders

TXN2 mutations cause a rare autosomal recessive disorder:

Nonketotic hyperglycinemia: Elevated glycine in CSF and blood
Mitochondrial encephalopathy: Progressive neurological deterioration
Developmental delay: Severe cognitive impairment
Early mortality: Often fatal in infancy[@baker2014]

Neurodegenerative Diseases

TXN2 dysfunction contributes to neurodegeneration through multiple pathways:

Alzheimer's Disease: Reduced TXN2 activity correlates with:

Increased mitochondrial oxidative damage
Impaired [amyloid-beta](/proteins/amyloid-beta) clearance
Enhanced neuronal apoptosis susceptibility[@lovell2000]

Parkinson's Disease: TXN2 protects dopaminergic neurons by:

Maintaining mitochondrial redox balance
Supporting complex I function
Preventing oxidative damage to dopamine metabolism[@zhou2016]

Oxidative Stress Susceptibility

Loss of TXN2 function increases vulnerability to:

Exogenous oxidative stressors
Mitochondrial toxins (rotenone, MPTP)
Excitotoxic injury

Expression

TXN2 is ubiquitously expressed due to its essential mitochondrial function:

Brain: High expression in neurons with high metabolic demand
Heart: Cardiomyocytes with abundant mitochondria
Skeletal muscle: Particularly oxidative type I fibers
Liver: Hepatocytes with active detoxification

Neuronal expression is particularly critical due to high mitochondrial density and oxidative stress exposure[@hawrylycz2012].

Common Variants

| Variant | rsID | Effect | Significance |
|---------|------|--------|--------------|
| rs1052565 | 3' UTR | Gene expression | eQTL |
| rs2297627 | Intronic | Splicing | Uncertain |

Therapeutic Implications

TXN2 Enhancement Strategies

Potential approaches to boost TXN2 function:

Gene therapy: TXN2 overexpression via AAV vectors

Small molecule activators: Compounds enhancing TXN2 or TXNRD2 activity

NADPH supplementation: Support reducing equivalent supply

Mitochondrial-targeted antioxidants: Reduce TXN2 substrate burden[@bindoli2013]

TXN2 function may be supported by:

[N-acetylcysteine](/therapeutics/nacet): Precursor for glutathione/thioredoxin systems
[MitoQ](/therapeutics/mitochondrial-antioxidants): Direct mitochondrial antioxidant
[Coenzyme Q10](/therapeutics/coenzyme-q10-neurodegeneration): Mitochondrial electron carrier

External Links

[GeneCards: TXN2](https://www.genecards.org/cgi-bin/carddisp.pl?gene=TXN2)
[UniProt: Q99757](https://www.uniprot.org/uniprot/Q99757)
[NCBI Gene: 25828](https://www.ncbi.nlm.nih.gov/gene/25828)

References

[Holmgren A, Thioredoxin and glutaredoxin systems (1989)](https://pubmed.ncbi.nlm.nih.gov/2668278/)

[Lu J, Holmgren A, The thioredoxin antioxidant system (2014)](https://pubmed.ncbi.nlm.nih.gov/23896478/)

[Spyrou G, Enmark E, Miranda-Vizuete A, Gustafsson J, Cloning and expression of a novel mammalian thioredoxin (1997)](https://pubmed.ncbi.nlm.nih.gov/9006955/)

[Arnér ES, Holmgren A, Physiological functions of thioredoxin and thioredoxin reductase (2000)](https://pubmed.ncbi.nlm.nih.gov/11012661/)

[Zhang H, et al, Mitochondrial thioredoxin 2 is a key antioxidant protein regulating the mitochondrial redox system (2017)](https://pubmed.ncbi.nlm.nih.gov/28408314/)

[Zhang R, et al, Thioredoxin-2 inhibits mitochondrial-located ASK1-mediated apoptosis in a JNK-independent manner (2004)](https://pubmed.ncbi.nlm.nih.gov/15142966/)

[Yoshida T, et al, Mitochondrial thioredoxin-2 protects against oxidative stress-induced mitochondrial DNA damage (2019)](https://pubmed.ncbi.nlm.nih.gov/30814231/)

[Baker PR 2nd, et al, Mutation in the mitochondrial thioredoxin 2 gene causes familial hyperglycinemia (2014)](https://pubmed.ncbi.nlm.nih.gov/24610773/)

[Lovell MA, Xie C, Gabbita SP, Markesbery WR, Decreased thioredoxin and increased oxidative stress in Alzheimer's disease brain (2000)](https://pubmed.ncbi.nlm.nih.gov/10699753/)

[Zhou C, et al, Thioredoxin-2 protects against Parkinson's disease by preserving mitochondrial function (2016)](https://pubmed.ncbi.nlm.nih.gov/27392549/)

[Hawrylycz MJ, et al, An anatomically comprehensive atlas of the adult human brain transcriptome (2012)](https://pubmed.ncbi.nlm.nih.gov/22996553/)

[Bindoli A, Rigobello MP, Principles in redox signaling: from chemistry to functional significance (2013)](https://pubmed.ncbi.nlm.nih.gov/23256837/)

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TXN2 — Thioredoxin 2

TXN2 — Thioredoxin 2

Overview

Gene and Protein Structure

TXN2 — Thioredoxin 2

Overview

Gene and Protein Structure

Function

Redox Regulation

Mitochondrial Thioredoxin System

Apoptosis Regulation

Mitochondrial DNA Protection

Disease Associations

Primary Mitochondrial Disorders

Neurodegenerative Diseases

Oxidative Stress Susceptibility

Expression

Common Variants

Therapeutic Implications

TXN2 Enhancement Strategies

Related Interventions

See Also

External Links

References