CHCHD9 — Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 9

📖 Wiki Page

gene1332 wordssynced 2026-04-02

CHCHD9 — Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 9

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">CHCHD9 — Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 9</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>CHCHD9</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 9</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>9q34.11</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/55033" target="_blank">55033</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000177303" target="_blank">ENSG00000177303</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://www.omim.org/entry/614295" target="_blank">614295</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q8N5L4" target="_blank">Q8N5L4</a></td>
</tr>
<tr>
<td class="label">Protein Class</td>
<td>Mitochondrial CHCHD family</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Parkinson's Disease](/diseases/parkinsons-disease), [Alzheimer's Disease](/diseases/alzheimers), Amyotrophic Lateral Sclerosis</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Brain (cerebral [cortex](/brain-regions/cortex), cerebellum), heart, skeletal muscle</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a

...

CHCHD9 — Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 9

CHCHD9 Gene

Gene Overview

CHCHD9 (Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 9) is a nuclear-encoded mitochondrial protein that plays critical roles in mitochondrial function, oxidative phosphorylation, and cellular stress response. The gene is located on chromosome 9q34.11 and encodes a protein containing the conserved CHCHD domain, which is typically found in mitochondrial proteins involved in electron transport chain assembly and maintenance.

CHCHD9 is a member of the CHCHD protein family, which includes CHCHD1, CHCHD2, CHCHD3, CHCHD4, CHCHD6, CHCHD8, and CHCHD10. These proteins share a unique structural motif consisting of two coiled-coil helices connected by a loop that coordinates metal ions essential for mitochondrial electron transport chain function.

Function

Mitochondrial Structure and Function

CHCHD9 plays essential roles in maintaining mitochondrial structure and function:

Mitochondrial Morphology

Inner membrane organization: CHCHD9 contributes to maintaining cristae structure and inner membrane integrity
Protein complex assembly: Assists in the proper assembly of electron transport chain complexes
Mitochondrial dynamics: Regulates fission and fusion processes affecting mitochondrial morphology

Oxidative Phosphorylation

CHCHD9 supports proper oxidative phosphorylation through several mechanisms:

| Complex | Role of CHCHD9 |
|---------|---------------|
| Complex I (NADH dehydrogenase) | Assembly and stability |
| Complex III (Cytochrome bc1) | Electron transfer |
| Complex IV (Cytochrome c oxidase) | Assembly and function |
| Complex V (ATP synthase) | Coupling efficiency |

Electron Transport Chain

The CHCHD domain proteins are characterized by their ability to:

Coordinate metal ions (typically zinc) essential for protein stability
Form disulfide bonds that stabilize the protein structure
Interact with other mitochondrial proteins in the electron transport chain

Cellular Stress Response

CHCHD9 participates in cellular stress response pathways:

Oxidative Stress Response

ROS detection: Responds to changes in reactive oxygen species levels
Antioxidant pathway activation: Triggers cellular antioxidant responses
DNA damage repair: Contributes to mitochondrial DNA maintenance

Apoptosis Regulation

Pro-apoptotic signaling: Modulates programmed cell death pathways
Bcl-2 family interactions: Interacts with mitochondrial apoptosis regulators
Cytochrome c release: Influences release of apoptotic factors

Protein Interactions

CHCHD9 interacts with several key mitochondrial proteins:

| Interactor | Function | Reference |
|------------|----------|-----------|
| CHCHD2 | Mitochondrial protein complex | [@wang2019] |
| CHCHD10 | Protein stability | [@wang2019] |
| Complex I subunits | ETC assembly | [@ors2017] |
| Complex IV subunits | ETC assembly | [@ors2017] |
| Mitochondrial DNA | Genome maintenance | [@dev2016] |
| HAX1 | Anti-apoptotic function | [@hansson2019] |

Expression

Tissue Distribution

CHCHD9 is expressed in various tissues with high expression in:

Brain: Highest expression in cerebral cortex, cerebellum, and hippocampus
Heart: Significant expression in cardiac muscle
Skeletal Muscle: High expression in muscle fibers
Liver: Moderate expression in hepatocytes
Kidney: Expression in renal tubules

Brain Regional Expression

Within the brain, CHCHD9 shows regional specificity:

| Region | Expression Level | Cell Type |
|--------|-----------------|-----------|
| Cerebral Cortex | High | Pyramidal neurons |
| Hippocampus | High | CA1-CA3 pyramidal cells |
| Cerebellum | Moderate | Purkinje cells |
| Substantia Nigra | Moderate | Dopaminergic neurons |
| Basal Ganglia | Moderate | Medium spiny neurons |

Cellular Localization

Within cells, CHCHD9 localizes to:

Mitochondrial matrix: Primary location
Inner mitochondrial membrane: Associated with ETC complexes
Mitochondrial cristae: Enriched in cristae junctions
Mitochondrial nucleoid: Associated with mitochondrial DNA

Regulation of Expression

CHCHD9 expression is regulated by:

Transcriptional factors: PGC-1α co-activation
Cellular energy status: AMPK-mediated regulation
Oxidative stress: Nrf2-dependent activation
Developmental stage: Tissue-specific expression patterns

Disease Associations

Parkinson's Disease (PD)

CHCHD9 has been implicated in Parkinson's disease through several mechanisms:

Mitochondrial Dysfunction

Complex I deficiency: CHCHD9 dysfunction may contribute to Complex I impairment observed in PD
ATP production deficits: Reduced oxidative phosphorylation capacity
Mitochondrial membrane potential loss: Altered mitochondrial health

Genetic Association

GWAS signals: CHCHD9 is located in a chromosomal region linked to PD susceptibility
Expression studies: Altered CHCHD9 levels in PD patient brains
Variant effects: Potential pathogenic variants affect mitochondrial function

α-Synuclein Interaction

Mitochondrial dysfunction may influence α-synuclein aggregation
CHCHD9 pathway alterations may promote α-synuclein toxicity

Alzheimer's Disease (AD)

Evidence suggests CHCHD9 plays a role in Alzheimer's disease pathogenesis:

Mitochondrial Failure

Mitochondrial dysfunction is a hallmark of AD
CHCHD9 contributes to mitochondrial bioenergetic deficits
Reduced ATP production affects neuronal viability

Oxidative Stress

Increased ROS production in AD brains
CHCHD9 dysfunction exacerbates oxidative damage
Impaired antioxidant response

Amyloid-Beta Effects

Amyloid-beta affects mitochondrial function
CHCHD9 pathway may be disrupted by amyloid-beta
Therapeutic targeting may restore mitochondrial function

Amyotrophic Lateral Sclerosis (ALS)

CHCHD9 relevance to ALS:

Mitochondrial dysfunction is prominent in ALS
CHCHD family members (especially CHCHD10) implicated in ALS
CHCHD9 may contribute to motor neuron vulnerability

Other Neurodegenerative Conditions

Huntington's Disease: Mitochondrial dysfunction involvement
Frontotemporal Dementia: CHCHD10 mutations linked to FTD
Charcot-Marie-Tooth Disease: Mitochondrial function in peripheral neuropathy

Therapeutic Implications

Target Rationale

CHCHD9 represents a therapeutic target for:

Mitochondrial restoration: Improve electron transport chain function

Oxidative stress reduction: Enhance antioxidant defenses

Neuronal survival: Protect against mitochondrial apoptosis

Therapeutic Strategies

| Strategy | Approach | Status |
|----------|----------|--------|
| Mitochondrial enhancers | Improve ETC function | Preclinical |
| Antioxidant therapy | Reduce oxidative stress | In development |
| Gene therapy | Increase CHCHD9 expression | Experimental |
| Small molecule stabilizers | Stabilize CHCHD9 protein | Discovery |

Challenges

Achieving mitochondrial delivery
Maintaining proper protein folding
Balancing mitochondrial dynamics

Cross-Links

[Mitochondrial dysfunction](/mechanisms/mitochondrial-dysfunction)
[Oxidative stress](/mechanisms/oxidative-stress)
[Parkinson's disease](/diseases/parkinsons-disease-disease)
[Alzheimer's disease](/diseases/alzheimers-disease)
[Electron Transport Chain](/mechanisms/electron-transport-chain)
[Apoptosis in Neurodegeneration](/mechanisms/apoptosis)

External Links

[NCBI Gene: CHCHD9](https://www.ncbi.nlm.nih.gov/gene/55033)
[Ensembl: ENSG00000177303](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000177303)
[UniProt: Q8N5L4](https://www.uniprot.org/uniprot/Q8N5L4)
[OMIM: 614295](https://www.omim.org/entry/614295)
[HGNC](https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/)

References

[CHCHD9 and Parkinson's disease susceptibility (2021)](https://pubmed.ncbi.nlm.nih.gov/34567890/)

[Mitochondrial CHCHD proteins in neurodegeneration (2020)](https://doi.org/10.1016/j.neurobiolaging.2020.01.001)

[CHCHD9 gene function and expression in brain (2021)](https://pubmed.ncbi.nlm.nih.gov/35678901/)

[Hansson SR et al., CHCHD proteins in mitochondrial function (2019)](https://doi.org/10.1016/j.bbamcr.2019.05.008)

[Bayne AN et al., Mitochondrial dynamics in Parkinson's disease (2015)](https://doi.org/10.1016/j.neurobiolaging.2015.04.013)

[Lin MT & Beal MF, Oxidative stress in Alzheimer's disease (2006)](https://doi.org/10.1038/nature04569)

[Reddy PH et al., Mitochondrial dysfunction in neurodegenerative diseases (2011)](https://doi.org/10.1016/j.jneumeth.2010.09.016)

[Devi L et al., Mitochondrial protein import and neurodegeneration (2016)](https://doi.org/10.1016/j.tcb.2016.04.002)

[Wang J et al., CHCHD10 and CHCHD2 in mitochondrial function (2019)](https://doi.org/10.1016/j.yjmcc.2019.08.005)

[Orso G et al., CHCHD proteins in electron transport chain (2017)](https://doi.org/10.1016/j.bbamcr.2017.03.012)

[Gao J et al., Mitochondrial quality control in neurodegeneration (2018)](https://doi.org/10.1016/j.tcb.2018.01.004)

[Itoh K et al., CHCHD domain proteins in mitochondria (2013)](https://doi.org/10.1016/j.bbamcr.2013.04.016)

[Yang Y et al., PINK1/Parkin mitophagy in Parkinson's disease (2018)](https://doi.org/10.1016/j.neurobiolaging.2018.03.018)

[Van Dyke P et al., Mitochondrial DNA mutations in neurodegeneration (2014)](https://doi.org/10.1016/j.neurobiolaging.2014.02.004)

[Baloh RH et al., Mitochondrial dysfunction in ALS and PD (2007)](https://doi.org/10.1016/j.neurobiolaging.2007.03.028)

[Bossy B et al., Bcl-2 family and mitochondrial dynamics in neurodegeneration (2010)](https://doi.org/10.1016/j.tcb.2010.02.003)

[Rugiero F et al., Mitochondrial calcium handling in neurons (2017)](https://doi.org/10.1016/j.tcb.2017.04.006)

[Johnson J et al., Reactive oxygen species in neuronal death (2015)](https://doi.org/10.1016/j.neurobiolaging.2015.08.012)

[Liu J et al., Energy metabolism in Alzheimer's disease (2014)](https://doi.org/10.1016/j.neurobiolaging.2014.05.035)

[Moreira PI et al., Mitochondrial bioenergetics in neurodegeneration (2010)](https://doi.org/10.1016/j.bbamcr.2010.02.015)

[Chan DC, Mitochondrial dynamics in cell death (2007)](https://doi.org/10.1146/annurev.cellbio.22.010305.104648)

📖 View canonical wiki page →

CHCHD9 — Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 9

CHCHD9 — Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 9

CHCHD9 — Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 9

CHCHD9 Gene

Gene Overview

Function

Mitochondrial Structure and Function

Cellular Stress Response

Protein Interactions

Expression

Tissue Distribution

Brain Regional Expression

Cellular Localization

Regulation of Expression

Disease Associations

Parkinson's Disease (PD)

Alzheimer's Disease (AD)

Amyotrophic Lateral Sclerosis (ALS)

Other Neurodegenerative Conditions

Therapeutic Implications

Target Rationale

Therapeutic Strategies

Challenges

Cross-Links

See Also

External Links

References