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

Gene ID: 1327, updated on 7-Apr-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
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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_2023_10 current GRCh38.p14 (GCF_000001405.40) 16 NC_000016.10 (85799695..85807068)
RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 16 NC_060940.1 (91865215..91872584)
105.20220307 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
  • 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. 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
  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. Active site intermediates in the reduction of O(2) by cytochrome oxidase, and their derivatives. Wikström M. Biochim Biophys Acta, 2012 Apr. PMID 22079200
  5. The mechanism for proton pumping in cytochrome c oxidase from an electrostatic and quantum chemical perspective. Blomberg MR, et al. Biochim Biophys Acta, 2012 Apr. PMID 21978537

See all (113) citations in PubMed

GeneRIFs: Gene References Into Functions

What's a GeneRIF?
  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. Studies suggest a model that links cell signaling with the phosphorylation state of Cytochrome c (Cytc) and cytochrome c oxidase (COX).
    Title: Regulation of mitochondrial respiration and apoptosis through cell signaling: cytochrome c oxidase and cytochrome c in ischemia/reperfusion injury and inflammation.
  10. Studies suggest that the main function of nuclear encoded subunits of cytochrome c oxidase appears to be "only" to control the activity of the mitochondrial subunits.
    Title: Cytochrome c oxidase: evolution of control via nuclear subunit addition.
Submit: New GeneRIF Correction See all GeneRIFs (18)

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
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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 membrane IDA
Inferred from Direct Assay
more info
 PubMed 
part_of mitochondrial respiratory chain complex IV IBA
Inferred from Biological aspect of Ancestor
more info
  
part_of mitochondrial respiratory chain complex IV IMP
Inferred from Mutant Phenotype
more info
 PubMed 
part_of mitochondrial respiratory chain complex IV IPI
Inferred from Physical Interaction
more info
 PubMed 
located_in mitochondrion HDA PubMed 
located_in mitochondrion IDA
Inferred from Direct Assay
more info
 PubMed 
located_in nucleoplasm IDA
Inferred from Direct Assay
more info
  

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_2023_10

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

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