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Symbol CHCHD4 contributors: shn, mct - updated : 21-11-2017
HGNC name coiled-coil-helix-coiled-coil-helix domain containing 4
HGNC id 26467
Location 3p25.1      Physical location : 14.153.577 - 14.166.371
Synonym name
  • mitochondrial intermembrane space import and assembly 40 homolog (S. cerevisiae)
  • translocase of inner mitochondrial membrane 40 homolog
  • Synonym symbol(s) FLJ31709, MIA40, TIMM40
    TYPE functioning gene
    STRUCTURE 12.80 kb     4 Exon(s)
    MAPPING cloned Y linked N status provisional
    Map pter - D3S3602 - D3S1585 - CHCHD4 - D3S1554 - D3S3595 - tel
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    3 splicing 1476 16 142 liver, kidney, lung, brain, heart and spleen 2012 22214851
  • CHCHD4-1
  • is the predominant transcript
  • identical to MIA40, the homolog of yeast Mia40, a key component of the mitochondrial disulfide relay system that regulates electron transfer to cytochrome c
  • 4 - 1646 17 155 liver, kidney, lung, brain, heart and spleen 2012 22214851
  • CHCHD4-2
    Type ubiquitous
       expressed in (based on citations)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveliver   highly
    Lymphoid/Immunespleen   moderately
    Nervousbrain   highly
    Respiratorylung   moderately
    Urinarykidney   highly
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularstriatumskeletal moderately
    cell lineage
    cell lines
    at STAGE
  • conserved coiled-coil-helix-coiled-coil-helix (CHCH) domain important for mitochondrial localization
  • the conserved cysteine motif in the C terminus but lacks the N-terminal transmembrane region and the mitochondrial targeting signal
  • has a 66-residue folded domain made of an a-helical
  • hairpin core and a rigid N-terminal lid, with a characteristic CPC motif
    interspecies ortholog to Chchd4, Rattus norvegicus
    ortholog to CHCHD4, Pan troglodytes
    ortholog to Chchd4, Mus musculus
    homolog to lypd6b, Danio rerio
  • protein family which share 6 a highly conserved cysteine residues constituting a -CXC-CX(9)C-CX(9)C- motif in the C terminus
  • CATEGORY regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    basic FUNCTION
  • a mitochondrial translocase that mediates the import of small molecules into the intermembrane space
  • involved in mitochondrial biogenesis, and switching the sorting pathway
  • oxidoreductase that does not have a thioredoxin domain plays a key role in oxidative protein folding in the mitochondrial intermembrane space
  • vital to allow a correct function of several mitochondrial processes: respiration and protein biogenesis
  • introduces disulfide bonds into imported precursor substrates after they cross the outer mitochondrial membrane protein import channel
  • works as an oxidoreductase and molecular chaperone to cause both disulfide bond formation
  • central component of a redox-sensitive mitochondrial intermembrane space import machinery
  • is an ineffective protein disulfide isomerase when its ability to restore enzymatic activity from scrambled RNase is compared to that of protein disulfide isomerase
  • iron-binding protein with the ability to bind iron
  • indispensable role for the export of Fe-S clusters from mitochondria
  • oxidoreductase CHCHD4 mediates disulfide bond formation and protein folding in the mitochondrial intermembrane space
  • CHCHD4 is a mitochondrial intermembrane space protein that plays a major role in the import of intermembrane proteins and physically interacts with apoptosis-inducing factor (AIFM1)
  • is required for perinuclear localization of mitochondria and HIF activation in response to long-term hypoxia
  • CELLULAR PROCESS protein, post translation, folding
    PHYSIOLOGICAL PROCESS mitochondrial transport
    text catalyzes disulfide-bond formation for both CX9C and CX3C proteins
    a component
  • disulfide relay system in the IMS (intermembrane space) has been identified which consists of two essential components, the sulfhydryl oxidase GFER and the redox-regulated import receptor CHCHD4
  • component of the mitochondrial Fe-S cluster export machinery
    small molecule
  • COX17 and Tim substrates
  • CIAPIN1 and CHCHD4 interact through an intermolecular disulfide-bonded intermediate and CIAPIN1 is imported into mitochondria
  • COX17 is a substrate of CHCHD4
  • CHCHD3 binds to CHCHD4 for further folding and assembly into macromolecular complexes
  • is necessary for the respiratory-dependent translocation of TP53 into the mitochondria
  • CHCHD4 levels could be restored in AIFM1-deficient cells by enforcing its AIFM1-independent mitochondrial localization
  • AIFM1 physically interacts with the oxidoreductase CHCHD4
  • among the interaction partners of CHDCHD4 is MICU1-the regulator of the mitochondrial Ca(2+) uniporter (MCU), which transfers Ca(2+) across the inner membrane
  • is the missing link between AIFM1 deficiency and dysfunctional biogenesis of respiratory chain complexes
  • FOXO3 binds to the CHCHD4 promoter and represses its expression, preventing the translocation of TP53 to the mitochondria and thereby increasing TP53 nuclear localization
  • intracellular distribution of the mitochondrial network is an important feature of the cellular response to hypoxia, contributing to hypoxic signaling via HIF activation and regulated by way of the cross talk between CHCHD4 and HIF1A
  • cell & other
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --other  
    CHCHD4 haploinsufficiency afforded persistent neuroprotection related to reduced release of mitochondrial intermembrane space proteins
    Variant & Polymorphism
    Candidate gene
    Therapy target
    targeting CHCHD4 expression blocked HIF1A induction and function in hypoxia and resulted in inhibition of tumor growth and angiogenesis
  • mice with a heterozygous knockout of Chchd4 exhibit reduced weight gain when fed with a Western style high-fat diet