CHCHD10 is a nuclear-encoded mitochondrial protein localized to the mitochondrial intermembrane space (IMS). It plays a critical role in maintaining mitochondrial cristae morphology and oxidative phosphorylation (OXPHOS) complex integrity. Mutations in CHCHD10 cause a broad clinical spectrum including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), mitochondrial myopathy, and cerebellar ataxia.
:: infobox .infobox-protein
| CHCHD10 Protein |
|
| Gene |
CHCHD10 |
| UniProt |
Q8WYQ3 |
| Molecular Weight |
~14 kDa |
| Subcellular Localization |
Mitochondrial intermembrane space |
| Protein Family |
Coiled-coil-helix-coiled-coil-helix (CHCH) domain family |
| Aliases |
Mitochondrial CHCHD10, JS-1 |
===
¶ Domain Architecture
CHCHD10 is a small mitochondrial protein (~110 amino acids) characterized by:
- N-terminal mitochondrial targeting sequence: Hydrophobic region for IMS import
- CHCH domain: Two coiled-coil-helix motifs with conserved cysteine residues
- C-terminal helix: Involved in protein-protein interactions
- Forms homodimers and heterodimers with CHCHD2
- Contains conserved twin CX9C motifs that coordinate metal ions
- Localizes to mitochondrial cristae junctions
¶ Mitochondrial Cristae Maintenance
CHCHD10 resides at cristae junctions within the mitochondrial intermembrane space, where it:
- Stabilizes the MICOS (Mitochondrial Contact Site and Cristae Organizing System)
- Maintains cristae morphology essential for efficient OXPHOS
- Interacts with CHCHD2 to form a functional complex
CHCHD10 is required for OXPHOS complex stability:
- Complex I (NADH dehydrogenase): Required for assembly and stability
- Complex IV (Cytochrome c oxidase): Critical for function
- Loss of CHCHD10 leads to impaired respiration and ATP depletion
- Mitochondrial network dynamics
- Calcium homeostasis in mitochondria
- Apoptosis regulation through mitochondrial pathway
CHCHD10 was identified as an ALS-FTD gene in 2014:
- Mutations: S59L, R15L, G66V, G58R, P34S
- Pathogenesis: Loss of mitochondrial function, impaired cristae, reduced OXPHOS
- Clinical phenotype: Motor neuron disease with rapid progression
- Overlap with FTD: Some patients develop frontotemporal dementia
- CHCHD10 mutations cause FTD in some families
- Often presents with behavioral variant FTD
- May co-occur with motor neuron symptoms
- Progressive muscle weakness
- Ragged-red fibers on muscle biopsy
- Exercise intolerance
- Progressive gait and limb ataxia
- Dysarthria and oculomotor abnormalities
- Often part of the ALS-FTD spectrum
- Cardiomyopathy reported in some mutation carriers
- May present as dilated cardiomyopathy
CHCHD10 interacts with:
- CHCHD2: Forms heterodimeric complex in mitochondria
- MICOS complex: Stabilizes cristae junctions
- OXPHOS complexes: I and IV stability
- Import machinery: TIMM complex
| Approach |
Description |
Status |
| Mitochondrial protectants |
CoQ10, idebenone |
Under investigation |
| Gene therapy |
AAV-CHCHD10 delivery |
Preclinical |
| Small molecule stabilizers |
MICOS stabilizers |
Research |
| Antioxidants |
Mitochondrial-targeted antioxidants |
Research |
- Display mitochondrial dysfunction
- Show motor deficits
- Impaired respiratory chain activity
- Express mutant CHCHD10
- Recapitulate ALS-FTD phenotypes