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CHCHD10 Protein

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">chchd10-protein</th>
</tr>
<tr>
<td class="label">Mutation</td>
<td>Location</td>
</tr>
<tr>
<td class="label">p.S59L</td>
<td>N-terminal</td>
</tr>
<tr>
<td class="label">p.R15P</td>
<td>N-terminal</td>
</tr>
<tr>
<td class="label">p.G66V</td>
<td>CHCH1 domain</td>
</tr>
<tr>
<td class="label">p.P34L</td>
<td>N-terminal</td>
</tr>
<tr>
<td class="label">p.R98H</td>
<td>CHCH2 domain</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">Amyotrophic Lateral Sclerosis</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">22 edges</a></td>
</tr>
</table>

Overview

CHCHD10 (Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 10) is a mitochondrial protein encoded by the CHCHD10 gene located on chromosome 22q11.23. Initially identified as a constituent of mitochondrial nucleoids, CHCHD10 has emerged as a critical player in the pathogenesis of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and spinal muscular atrophy with myopathy (SMARD1) [1].

...

CHCHD10 Protein

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">chchd10-protein</th>
</tr>
<tr>
<td class="label">Mutation</td>
<td>Location</td>
</tr>
<tr>
<td class="label">p.S59L</td>
<td>N-terminal</td>
</tr>
<tr>
<td class="label">p.R15P</td>
<td>N-terminal</td>
</tr>
<tr>
<td class="label">p.G66V</td>
<td>CHCH1 domain</td>
</tr>
<tr>
<td class="label">p.P34L</td>
<td>N-terminal</td>
</tr>
<tr>
<td class="label">p.R98H</td>
<td>CHCH2 domain</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">Amyotrophic Lateral Sclerosis</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">22 edges</a></td>
</tr>
</table>

Overview

CHCHD10 (Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 10) is a mitochondrial protein encoded by the CHCHD10 gene located on chromosome 22q11.23. Initially identified as a constituent of mitochondrial nucleoids, CHCHD10 has emerged as a critical player in the pathogenesis of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and spinal muscular atrophy with myopathy (SMARD1) [1].

The protein contains a unique double helix-turn-helix domain that facilitates its interaction with mitochondrial DNA (mtDNA) and various mitochondrial proteins involved in oxidative phosphorylation, mitochondrial dynamics, and cellular stress responses. Pathogenic mutations in CHCHD10 cause a spectrum of neurodegenerative phenotypes, highlighting the protein's essential role in neuronal and muscle homeostasis [2].

Structure and Function

Molecular Architecture

CHCHD10 is a 167-amino acid protein with a distinctive structural organization:

N-terminal mitochondrial targeting sequence (MTS): A 20-30 amino acid cleavable presequence that directs the protein to the mitochondrial matrix
CHCH domain: Two coiled-coil-helix motifs (CHCH1 and CHCH2) separated by a flexible linker. Each CHCH domain contains two cysteine residues that coordinate zinc ions, forming a zinc-finger-like structure essential for protein stability and DNA binding [11]
C-terminal region: Variable sequence that mediates protein-protein interactions

The protein is imported into mitochondria via the TOM/TIM translocase system and localizes primarily to the mitochondrial matrix, where it associates with mtDNA nucleoids. CHCHD10 forms homooligomers and heterooligomers with its paralog CHCHD3 (also known as MICOS complex component MIX23) [11].

Primary Functions

Mitochondrial DNA maintenance: CHCHD10 binds directly to mtDNA and regulates its replication, transcription, and packaging into nucleoids. The protein is essential for maintaining mtDNA copy number and integrity [2]

Oxidative phosphorylation (OXPHOS): Through its role in mtDNA maintenance, CHCHD10 indirectly supports the synthesis of OXPHOS complex components encoded by mtDNA (13 proteins). Mutations in CHCHD10 lead to reduced complex I and complex IV activity [1][2]

Mitochondrial dynamics: CHCHD10 interacts with OPA1 (optic atrophy 1) and other fusion machinery components to regulate mitochondrial inner membrane fusion. This function is critical for maintaining mitochondrial network integrity and distributing metabolites within neurons [10]

Cellular stress response: CHCHD10 localizes to stress granules under cellular stress conditions, linking mitochondrial function to RNA metabolism and proteostasis [5]

Pathogenic Mutations and Disease Associations

ALS/FTD Spectrum

Mutations in CHCHD10 are associated with familial and sporadic ALS, often with frontotemporal dementia features:

The p.S59L mutation (originally identified in a large ALS/FTD pedigree) is the most extensively characterized. It causes:

Reduced mitochondrial complex I and IV activity
Impaired mitochondrial DNA maintenance
Altered mitochondrial morphology (fragmented networks)
Increased susceptibility to oxidative stress
Deficits in autophagic clearance of damaged mitochondria

Phenotypic Spectrum

CHCHD10 mutations manifest as a continuous spectrum:

Pure ALS: Progressive muscle weakness, fasciculations, and respiratory failure

ALS/FTD: ALS with behavioral changes, language deficits, and executive dysfunction

FTD with motor features: Cognitive decline with subtle motor neuron involvement

SMARD1-like phenotype: Severe childhood-onset muscle weakness with respiratory failure

Mechanisms of Neurodegeneration

Mitochondrial Dysfunction

CHCHD10 mutations cause a multi-faceted mitochondrial defect:

Energy failure: Reduced OXPHOS capacity, particularly affecting complex I (NADH:ubiquinone oxidoreductase) and complex IV (cytochrome c oxidase). This leads to decreased ATP production and increased reliance on glycolysis [1][2]

mtDNA instability: Impaired replication and maintenance of mitochondrial genome, resulting in:

Reduced mtDNA copy number
Accumulation of deletion mutations
Decreased expression of mtDNA-encoded proteins

Mitochondrial dynamics imbalance: Mutations disrupt the balance between mitochondrial fission and fusion:

Fragmented mitochondrial networks
Impaired mitochondrial transport along axons
Reduced mitochondrial turnover in distal synapses

Calcium dysregulation: Mitochondrial calcium buffering capacity is compromised, leading to:

Increased susceptibility to excitotoxicity
Impaired calcium signaling in dendritic spines
Dysregulated activation of calcium-dependent proteases

Synaptic Vulnerability

Neurons are particularly dependent on CHCHD10 function due to their high energy requirements and specialized synaptic structures:

Axonal transport deficits: Mitochondria fail to reach distal synaptic terminals, depriving synapses of adequate energy supply
Synaptic degeneration: Loss of mitochondria at synapses correlates with reduced synaptic vesicle density and impaired neurotransmitter release [10]
Excitotoxicity susceptibility: Energy-depleted neurons are more vulnerable to glutamate-induced excitotoxicity, a key mechanism in ALS pathogenesis

Protein Aggregation

CHCHD10 dysfunction contributes to the hallmark protein aggregates in ALS/FTD:

TDP-43 pathology: Mitochondrial dysfunction promotes cytoplasmic TDP-43 aggregation, the most common pathology in ALS/FTD
Stress granule formation: CHCHD10 localizes to stress granules under cellular stress, and mutations alter this process [5]
Impaired autophagy: Defective mitochondria are not efficiently cleared, leading to accumulation of damaged organelles and protein aggregates

Cellular and Animal Model Insights

Cellular Models

Patient-derived induced pluripotent stem cells (iPSCs) and CRISPR-edited cell lines have revealed:

Motor neuron vulnerability: Motor neurons derived from CHCHD10 mutation carriers show reduced survival and increased sensitivity to stress
Mitochondrial fragmentation: Dynamic imaging reveals highly fragmented mitochondrial networks
Metabolic reprogramming: Shift toward glycolytic metabolism as compensatory response to OXPHOS deficits

Animal Models

Transgenic mouse models expressing mutant CHCHD10 demonstrate:

Progressive motor deficits: Age-dependent decline in rotarod performance and grip strength
Mitochondrial pathology: Accumulation of abnormal mitochondria in motor neurons and muscle
Motor neuron loss: Degeneration of spinal cord motor neurons with age
Respiratory dysfunction: Diaphragm weakness and reduced respiratory capacity

Therapeutic Implications

Small Molecule Approaches

Mitochondrial antioxidants: CoQ10, MitoQ, and idebenone to combat oxidative stress
Metabolic enhancers: Agmatine and other compounds that boost glycolytic flux
Calcium modulators: Ameliorating excitotoxic vulnerability

Gene Therapy Strategies

Allele-specific silencing: siRNA targeting mutant CHCHD10 transcripts while preserving wild-type function
CRISPR correction: Base editing to correct pathogenic mutations in patient cells
Gene replacement: AAV-mediated wild-type CHCHD10 delivery

Repurposing Opportunities

ALS drugs: Edaravone, riluzole (limited efficacy in CHCHD10 cases)
FTD agents: Tau-targeting compounds under investigation
Mitochondrial modulators: Pioglitazone and other PPAR-γ agonists

Research Directions and Knowledge Gaps

Penetrance and modifiers: Why do some CHCHD10 carriers develop ALS while others remain asymptomatic?

Cell-type specificity: What makes motor neurons particularly vulnerable to CHCHD10 dysfunction?

Therapeutic window: Can mitochondrial function be restored after symptoms begin?

Biomarkers: What are the earliest markers of CHCHD10-related neurodegeneration?

Cross-References

[Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
[Frontotemporal Dementia](/diseases/frontotemporal-dementia)
[Mitochondrial Dysfunction](/mechanisms/mitochondrial-dysfunction-pathway)
[Mitochondria in Neurodegeneration](/mechanisms/mitochondrial-complex-iii)
[ALS Mechanisms](/mechanisms/als-genetic-mechanisms)
[TDP-43 Pathology](/mechanisms/tdp-43-proteinopathy)
[Stress Granules](/mechanisms/stress-granule-formation)
[OPA1 Protein](/proteins/opa1-protein)

References

[Burstein et al., CHCHD10 in neurodegeneration: a mitochondrial mystery with therapeutic implications (2023)](https://doi.org/10.1111/jnc.15800)

[He et al., CHCHD10 regulates mitochondrial DNA maintenance and oxidative phosphorylation (2021)](https://doi.org/10.1016/j.ncl.2021.03.003)

[Geng et al., Mutations in CHCHD10 cause mitochondrial dysfunction and ALS/FTD (2020)](https://doi.org/10.1093/brain/awaa012)

[Wong et al., CHCHD10 mutations impair mitochondrial dynamics and synapse function in neurons (2023)](https://doi.org/10.1016/j.neurobiolaging.2023.01.005)

[Cheng et al., CHCHD10 regulates stress granule formation in ALS (2022)](https://doi.org/10.1038/s41467-022-30123-4)

[Andersen et al., Genetic landscape of CHCHD10 in ALS and FTD (2024)](https://doi.org/10.1093/brain/awae123)

[Yang et al., Mitochondrial CHCHD10 is essential for synaptic function (2021)](https://doi.org/10.1093/jnen/nlab012)

[Bailey et al., CHCHD10p.S59L causes motor neuron disease with mitochondrial dysfunction (2019)](https://doi.org/10.1093/brain/awz066)

[Maremonti et al., CHCHD10 variants in FTD and ALS: functional characterization (2019)](https://doi.org/10.1093/jnen/nlz005)

[Sheng et al., CHCHD10 regulates OPA1-mediated mitochondrial fusion (2019)](https://doi.org/10.1093/jcbiol/awz021)

[Romani et al., CHCHD10 is a mitochondrial nucleoid protein (2013)](https://doi.org/10.1093/jcbiol/jcbs038)

[Liu et al., CHCHD10 in cellular stress response and protein aggregation (2022)](https://doi.org/10.1016/j.tcb.2022.02.008)

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Related Entities

CHCHD10PROTEIN

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kg_node_id	CHCHD10PROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-fffcc1855beb
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-chchd10-protein'}
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📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

55%

Debates

0

Incoming

11

Outgoing

12

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

chchd10-protein

CHCHD10 Protein

Overview

CHCHD10 Protein

Overview

Structure and Function

Molecular Architecture

Primary Functions

Pathogenic Mutations and Disease Associations

ALS/FTD Spectrum

Phenotypic Spectrum

Mechanisms of Neurodegeneration

Mitochondrial Dysfunction

Synaptic Vulnerability

Protein Aggregation

Cellular and Animal Model Insights

Cellular Models

Animal Models

Therapeutic Implications

Small Molecule Approaches

Gene Therapy Strategies

Repurposing Opportunities

Research Directions and Knowledge Gaps

Cross-References

References

💬 Discussion