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.
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Structure
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
Structural Features
Forms homodimers and heterodimers with CHCHD2
Contains conserved twin CX9C motifs that coordinate metal ions
Localizes to mitochondrial cristae junctions
Normal Function
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
Oxidative Phosphorylation Regulation
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
Cellular Functions
Mitochondrial network dynamics
Calcium homeostasis in mitochondria
Apoptosis regulation through mitochondrial pathway
Role in Disease
Amyotrophic Lateral Sclerosis (ALS)
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
Frontotemporal Dementia (FTD)
CHCHD10 mutations cause FTD in some families
Often presents with behavioral variant FTD
May co-occur with motor neuron symptoms
Mitochondrial Myopathy
Progressive muscle weakness
Ragged-red fibers on muscle biopsy
Exercise intolerance
Cerebellar Ataxia
Progressive gait and limb ataxia
Dysarthria and oculomotor abnormalities
Often part of the ALS-FTD spectrum
Cardiac Involvement
Cardiomyopathy reported in some mutation carriers
May present as dilated cardiomyopathy
Protein-Protein Interactions
CHCHD10 interacts with:
CHCHD2: Forms heterodimeric complex in mitochondria
MICOS complex: Stabilizes cristae junctions
OXPHOS complexes: I and IV stability
Import machinery: TIMM complex
Therapeutic Implications
Animal Models
Chchd10 Knockout Mice
Display mitochondrial dysfunction
Show motor deficits
Impaired respiratory chain activity
Transgenic Models
Express mutant CHCHD10
Recapitulate ALS-FTD phenotypes
See Also
[CHCHD10 Gene](/genes/chchd10)
[Mitochondrial Dysfunction in ALS](/mechanisms/mitochondrial-dysfunction)