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    COX4I1 cytochrome c oxidase subunit 4I1 [ Homo sapiens (human) ]

    Gene ID: 1327, updated on 28-Oct-2024

    Summary

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    Official Symbol
    COX4I1provided by HGNC
    Official Full Name
    cytochrome c oxidase subunit 4I1provided by HGNC
    Primary source
    HGNC:HGNC:2265
    See related
    Ensembl:ENSG00000131143 MIM:123864; AllianceGenome:HGNC:2265
    Gene type
    protein coding
    RefSeq status
    REVIEWED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Also known as
    COX4; COXIV; COX4-1; COXIV-1; MC4DN16; COX IV-1
    Summary
    Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial respiratory chain. It is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane. The complex consists of 13 mitochondrial- and nuclear-encoded subunits. The mitochondrially-encoded subunits perform the electron transfer and proton pumping activities. The functions of the nuclear-encoded subunits are unknown but they may play a role in the regulation and assembly of the complex. This gene encodes the nuclear-encoded subunit IV isoform 1 of the human mitochondrial respiratory chain enzyme. It is located at the 3' of the NOC4 (neighbor of COX4) gene in a head-to-head orientation, and shares a promoter with it. Pseudogenes related to this gene are located on chromosomes 13 and 14. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]
    Expression
    Ubiquitous expression in heart (RPKM 267.7), duodenum (RPKM 151.5) and 25 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    See COX4I1 in Genome Data Viewer
    Location:
    16q24.1
    Exon count:
    6
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 16 NC_000016.10 (85799695..85807068)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 16 NC_060940.1 (91865215..91872584)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 16 NC_000016.9 (85833301..85840674)

    Chromosome 16 - NC_000016.10Genomic Context describing neighboring genes Neighboring gene ER membrane protein complex subunit 8 Neighboring gene RNA, U1 small nuclear 103, pseudogene Neighboring gene uncharacterized LOC101928557 Neighboring gene H3K27ac hESC enhancer GRCh37_chr16:85832503-85833109 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 7823 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 7824 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 7825 Neighboring gene NANOG-H3K27ac hESC enhancer GRCh37_chr16:85841166-85841873 Neighboring gene iron-sulfur cluster assembly 1 homolog (S. cerevisiae) pseudogene Neighboring gene ribosomal protein L10a pseudogene 12

    Genomic regions, transcripts, and products

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    Go to nucleotide: Graphics FASTA GenBank

    Expression

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    • Project title: HPA RNA-seq normal tissues HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4 07:08:55 2018

    Bibliography

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    Related articles in PubMed

    1. Regulation of mitochondrial respiration and apoptosis through cell signaling: cytochrome c oxidase and cytochrome c in ischemia/reperfusion injury and inflammation. Hüttemann M, et al. Biochim Biophys Acta, 2012 Apr. PMID 21771582, Free PMC Article
    2. Myocardial insufficiency is related to reduced subunit 4 content of cytochrome c oxidase. Vogt S, et al. J Cardiothorac Surg, 2018 Sep 17. PMID 30223867, Free PMC Article
    3. Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia. Abu-Libdeh B, et al. Eur J Hum Genet, 2017 Oct. PMID 28766551, Free PMC Article
    4. Replicative Stress Coincides with Impaired Nuclear DNA Damage Response in COX4-1 Deficiency. Douiev L, et al. Int J Mol Sci, 2022 Apr 8. PMID 35456968, Free PMC Article
    5. Active site intermediates in the reduction of O(2) by cytochrome oxidase, and their derivatives. Wikström M. Biochim Biophys Acta, 2012 Apr. PMID 22079200

    See all (127) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. The ratio of cytochrome c oxidase subunit 4 isoform 4I1 and 4I2 mRNA is changed in permanent atrial fibrillation.
      Title: The ratio of cytochrome c oxidase subunit 4 isoform 4I1 and 4I2 mRNA is changed in permanent atrial fibrillation.
    2. Cytochrome c oxidase IV isoform 1 (COX4-1) regulates the proliferation, migration and invasion of trophoblast cells via modulating mitochondrial function.
      Title: Cytochrome c oxidase IV isoform 1 (COX4-1) regulates the proliferation, migration and invasion of trophoblast cells via modulating mitochondrial function.
    3. Replicative Stress Coincides with Impaired Nuclear DNA Damage Response in COX4-1 Deficiency.
      Title: Replicative Stress Coincides with Impaired Nuclear DNA Damage Response in COX4-1 Deficiency.
    4. Upregulation of COX4-2 via HIF-1alpha in Mitochondrial COX4-1 Deficiency.
      Title: Upregulation of COX4-2 via HIF-1α in Mitochondrial COX4-1 Deficiency.
    5. In case of myocardial insufficiency and dilated cardiomyopathy, decreased expression of COX 4 results in an impaired CytOx activity. Higher enzymatic activity but equal oxygen consumption contribute to the pathophysiology of the myocardial insufficiency and appears as an indicator of oxidative stress. This kind of dysregulation should be in the focus for the development of diagnostic and therapy procedures
      Title: Myocardial insufficiency is related to reduced subunit 4 content of cytochrome c oxidase.
    6. COX4I1 variant K101N was identified in a patient with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia.
      Title: Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia.
    7. This cohort study showed that the COX411 gene was down regulation between patients with idiopathic Parkinson disease and controls
      Title: Analysis of blood-based gene expression in idiopathic Parkinson disease.
    8. We provide evidence that COX4-1 controls BMI1 expression via a redox mechanism
      Title: Nuclear-encoded cytochrome c oxidase subunit 4 regulates BMI1 expression and determines proliferative capacity of high-grade gliomas.
    9. COXIV mRNA (1.6 fold; P<0.01) and COXIV protein expression (1.5 fold; P<0.05) were increased by training but COXIV protein expression was decreased (20%; P<0.01) by acute exercise pre- and post-training.
      Title: Short-term intensified cycle training alters acute and chronic responses of PGC1α and Cytochrome C oxidase IV to exercise in human skeletal muscle.
    10. COX activity (electron transport complex IV) is reduced by 29% in maternal history of Alzheimer's disease compared to normal controls, and by 30% compared to paternal history of Alzheimer's disease.
      Title: Reduced mitochondria cytochrome oxidase activity in adult children of mothers with Alzheimer's disease.
    Submit: New GeneRIF Correction See all GeneRIFs (20)

    Phenotypes

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    Find tests for this gene in the NIH Genetic Testing Registry (GTR)

    Review eQTL and phenotype association data in this region using PheGenI

    Associated conditions

    Description Tests
    Mitochondrial complex 4 deficiency, nuclear type 16
    MedGen: C5436714 OMIM: 619060 GeneReviews: Not available
    		Compare labs

    EBI GWAS Catalog

    Description
    Discovery of six new susceptibility loci and analysis of pleiotropic effects in leprosy.
    EBI GWAS Catalog
    Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans.
    EBI GWAS Catalog

    Variation

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    See variants in ClinVar

    See studies and variants in dbVar

    See Variation Viewer (GRCh37.p13)

    See Variation Viewer (GRCh38)

    Genotypes

    HIV-1 interactions

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    Protein interactions

    Protein Gene Interaction Pubs
    Envelope surface glycoprotein gp160, precursor env HIV-1 gp160 is identified to have a physical interaction with cytochrome c oxidase subunit IV isoform 1 (COX4I1) in human HEK293 and/or Jurkat cell lines by using affinity tagging and purification mass spectrometry analyses PubMed
    Envelope transmembrane glycoprotein gp41 env HIV-1 gp41 is identified to have a physical interaction with cytochrome c oxidase subunit IV isoform 1 (COX4I1) in human HEK293 and/or Jurkat cell lines by using affinity tagging and purification mass spectrometry analyses PubMed
    Tat tat Tat-induced mitochondrial membrane permeabilization is associated with inhibition of cytochrome c oxidase (COX) activity by Tat in disrupted mitochondria from human samples PubMed
    Vpr vpr HIV-1 Vpr and FAT10 co-localize to mitochondria with marker protein Cox4 PubMed

    Go to the HIV-1, Human Interaction Database

    Pathways from PubChem

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    Interactions

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    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

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    Markers

    Homology

    Clone Names

    • FLJ23483, MGC72016

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables cytochrome-c oxidase activity TAS
    Traceable Author Statement
    more info
    		 PubMed 
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    Process Evidence Code Pubs
    involved_in cellular respiration NAS
    Non-traceable Author Statement
    more info
    		 PubMed 
    involved_in generation of precursor metabolites and energy TAS
    Traceable Author Statement
    more info
    		 PubMed 
    involved_in mitochondrial electron transport, cytochrome c to oxygen IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in mitochondrial electron transport, cytochrome c to oxygen NAS
    Non-traceable Author Statement
    more info
    		 PubMed 
    involved_in proton transmembrane transport IEA
    Inferred from Electronic Annotation
    more info
    		  
    Component Evidence Code Pubs
    located_in cytosol IEA
    Inferred from Electronic Annotation
    more info
    		  
    located_in membrane HDA PubMed 
    located_in mitochondrial inner membrane ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    located_in mitochondrial inner membrane TAS
    Traceable Author Statement
    more info
    		  
    located_in mitochondrial intermembrane space TAS
    Traceable Author Statement
    more info
    		  
    located_in mitochondrial membrane IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in mitochondrion HDA PubMed 
    located_in mitochondrion HTP PubMed 
    located_in mitochondrion IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in nucleoplasm IDA
    Inferred from Direct Assay
    more info
    		  
    part_of respiratory chain complex IV IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    part_of respiratory chain complex IV IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 

    General protein information

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    Preferred Names
    cytochrome c oxidase subunit 4 isoform 1, mitochondrial
    Names
    cytochrome c oxidase polypeptide IV
    cytochrome c oxidase subunit IV
    NP_001305715.1
    NP_001305717.1
    NP_001305723.1
    NP_001305726.1
    NP_001305731.1
    NP_001852.1
    XP_024305924.1
    XP_047289579.1

    NCBI Reference Sequences (RefSeq)

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    RefSeqs maintained independently of Annotated Genomes

    These reference sequences exist independently of genome builds. Explain

    These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

    Genomic

    1. NG_042280.1 RefSeqGene

      Range
      5129..12502
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. NM_001318786.3 → NP_001305715.1  cytochrome c oxidase subunit 4 isoform 1, mitochondrial isoform 1 precursor

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) differs in the 5' UTR, compared to variant 1. Variants 1 and 2 encode the same isoform (1).
      Source sequence(s)
      AC018695, BC047869, BE615615, BE728651, BM835194, BU599266, U90915
      Consensus CDS
      CCDS10955.1
      UniProtKB/Swiss-Prot
      B2R4J2, D3DUM7, P13073, Q6P666
      Related
      ENSP00000457015.1, ENST00000561569.5
      Conserved Domains (1) summary
      pfam02936
      Location:36 → 168
      COX4; Cytochrome c oxidase subunit IV

    2. NM_001318788.2 → NP_001305717.1  cytochrome c oxidase subunit 4 isoform 1, mitochondrial isoform 2 precursor

      Status: REVIEWED

      Description
      Transcript Variant: This variant (3) uses an alternate splice site in the 3' coding region, resulting in a frameshift and an early stop codon, compared to variant 1. It encodes isoform 2, which has a shorter and distinct C-terminus, compared to isoform 1.
      Source sequence(s)
      BE615615, BP343428, BU599266, U90915
      UniProtKB/TrEMBL
      H3BN72
      Conserved Domains (1) summary
      cd00922
      Location:26 → 126
      Cyt_c_Oxidase_IV; Cytochrome c oxidase subunit IV. Cytochrome c oxidase (CcO), the terminal oxidase in the respiratory chains of eukaryotes and most bacteria, is a multi-chain transmembrane protein located in the inner membrane of mitochondria and the cell membrane of ...

    3. NM_001318794.2 → NP_001305723.1  cytochrome c oxidase subunit 4 isoform 1, mitochondrial isoform 3 precursor

      Status: REVIEWED

      Description
      Transcript Variant: This variant (4) uses an alternate splice site in the 3' coding region, resulting in a different 3' coding region and 3' UTR, compared to variant 1. It encodes isoform 3, which has a shorter and distinct C-terminus, compared to isoform 1.
      Source sequence(s)
      AC018695, BC062437, BE615615, BG614492, BM835194, BU599266, CN406213
      Consensus CDS
      CCDS82020.1
      UniProtKB/TrEMBL
      H3BN72, H3BNV9
      Related
      ENSP00000455030.1, ENST00000568794.5
      Conserved Domains (1) summary
      cd00922
      Location:26 → 124
      Cyt_c_Oxidase_IV; Cytochrome c oxidase subunit IV. Cytochrome c oxidase (CcO), the terminal oxidase in the respiratory chains of eukaryotes and most bacteria, is a multi-chain transmembrane protein located in the inner membrane of mitochondria and the cell membrane of ...

    4. NM_001318797.3 → NP_001305726.1  cytochrome c oxidase subunit 4 isoform 1, mitochondrial isoform 4

      Status: REVIEWED

      Description
      Transcript Variant: This variant (5) differs in the 5' UTR, lacks a portion of the 5' coding region and uses a downstream start codon, compared to variant 1. It encodes isoform 4, which is shorter at the N-terminus, compared to isoform 1.
      Source sequence(s)
      AC018695, BE615615, BE728651, BU599266, DB502762, U90915
      UniProtKB/TrEMBL
      H3BPG0
      Related
      ENSP00000455301.1, ENST00000566405.5
      Conserved Domains (1) summary
      pfam02936
      Location:1 → 130
      COX4; Cytochrome c oxidase subunit IV

    5. NM_001318802.2 → NP_001305731.1  cytochrome c oxidase subunit 4 isoform 1, mitochondrial isoform 5

      Status: REVIEWED

      Description
      Transcript Variant: This variant (6) differs in the 5' and 3' UTRs and 5' and 3' coding regions, compared to variant 1. It encodes isoform 5, which is shorter and has distinct N- and C-termini, compared to isoform 1.
      Source sequence(s)
      BE615615, BM835194, BU599266, CD677397, U90915
      UniProtKB/Swiss-Prot
      P13073
      Conserved Domains (1) summary
      cl02792
      Location:21 → 65
      Cyt_c_Oxidase_IV; Cytochrome c oxidase subunit IV. Cytochrome c oxidase (CcO), the terminal oxidase in the respiratory chains of eukaryotes and most bacteria, is a multi-chain transmembrane protein located in the inner membrane of mitochondria and the cell membrane of ...

    6. NM_001861.6 → NP_001852.1  cytochrome c oxidase subunit 4 isoform 1, mitochondrial isoform 1 precursor

      See identical proteins and their annotated locations for NP_001852.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) encodes the longest isoform (1). Variants 1 and 2 encode the same isoform (1).
      Source sequence(s)
      AC018695, BC062437, BE615615, BM835194, BU599266
      Consensus CDS
      CCDS10955.1
      UniProtKB/Swiss-Prot
      B2R4J2, D3DUM7, P13073, Q6P666
      Related
      ENSP00000253452.2, ENST00000253452.8
      Conserved Domains (1) summary
      pfam02936
      Location:36 → 168
      COX4; Cytochrome c oxidase subunit IV

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000016.10 Reference GRCh38.p14 Primary Assembly

      Range
      85799695..85807068
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_024450156.2 → XP_024305924.1  cytochrome c oxidase subunit 4 isoform 1, mitochondrial isoform X1

      Conserved Domains (1) summary
      pfam02936
      Location:42 → 174
      COX4; Cytochrome c oxidase subunit IV

    2. XM_047433623.1 → XP_047289579.1  cytochrome c oxidase subunit 4 isoform 1, mitochondrial isoform X2

      UniProtKB/Swiss-Prot
      B2R4J2, D3DUM7, P13073, Q6P666

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060940.1 Alternate T2T-CHM13v2.0

      Range
      91865215..91872584
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)
    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    P13073.1 GenPept UniProtKB/Swiss-Prot:P13073

    Gene LinkOut

    The following LinkOut resources are supplied by external providers. These providers are responsible for maintaining the links.

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