Affinage

COX4I1

Cytochrome c oxidase subunit 4 isoform 1, mitochondrial · UniProt P13073

Round 2 corrected
Length
169 aa
Mass
19.6 kDa
Annotated
2026-04-28
63 papers in source corpus 20 papers cited in narrative 20 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

COX4I1 encodes the ubiquitous isoform 1 of subunit 4 of mitochondrial cytochrome c oxidase (complex IV), serving as a nuclear-encoded regulatory subunit essential for complex IV assembly, stability, and respiratory efficiency. Under normoxia COX4-1 is the predominant isoform; hypoxia triggers HIF-1-dependent transcriptional activation of COX4-2 and LON-mediated degradation of COX4-1, switching subunit composition to optimize ATP production and limit ROS (PMID:17418790). COX4-1 promotes assembly of respiratory supercomplexes, and its complete loss abolishes complex IV, secondarily impairs complex I biogenesis and mitochondrial translation, causes replicative stress with defective DNA damage repair, and in cancer cells rewires redox metabolism to favor apoptosis over ferroptosis (PMID:33578848, PMID:35478774, PMID:35456968, PMID:41596099). Biallelic loss-of-function mutations in COX4I1 cause cytochrome c oxidase deficiency presenting as mitochondrial disease, confirmed by lentiviral rescue of enzymatic activity in patient fibroblasts (PMID:28766551).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2006 High

    Establishing that COX4 translation is controlled by mitochondrial lipid composition resolved how nuclear-encoded respiratory subunit expression responds to organelle state, revealing a 5′-UTR stem-loop cis-element and a trans-acting cytoplasmic repressor protein active in cardiolipin-deficient yeast.

    Evidence Reporter fusions, 5′-UTR deletion mapping, and RNA-binding protein pulldown in pgs1Δ yeast

    PMID:16428432

    Open questions at the time
    • Identity of the cytoplasmic RNA-binding repressor protein was not determined
    • Whether this translational regulation operates in mammalian cells is unknown
  2. 2007 High

    Demonstrating that HIF-1 coordinately activates COX4-2 and the LON protease to degrade COX4-1 under hypoxia established the first oxygen-responsive isoform-switching mechanism for a respiratory chain subunit, directly linking subunit composition to ATP yield and ROS output.

    Evidence Transcriptional reporters, siRNA, overexpression, O₂ consumption, ATP, and ROS assays in mammalian cells

    PMID:17418790

    Open questions at the time
    • Tissue-specific kinetics and thresholds of the isoform switch in vivo are incompletely defined
    • Whether post-translational modifications modulate the switching efficiency is unresolved
  3. 2007 High

    Solving the NMR structure of yeast Cox4 and showing that Zn(II) coordination by conserved Cys/His residues is essential for complex IV assembly provided the first structural basis for the subunit's role in enzyme stability.

    Evidence NMR solution structure, site-directed mutagenesis of Zn-ligand residues, yeast complementation

    PMID:17215247

    Open questions at the time
    • Whether Zn coordination is functionally conserved in human COX4I1 has not been directly tested by mutagenesis
    • No high-resolution structure of the isolated human COX4I1 subunit exists
  4. 2012 High

    Identifying COX4I1 as an early-assembling subunit integrated via TIM21-mediated coupling of the TIM23 translocase to MITRAC assembly intermediates explained how mitochondrial import is coordinated with respiratory chain biogenesis.

    Evidence AP-MS of COX assembly intermediates, TIM21 knockdown, pulse-chase metabolic labeling, BN-PAGE in human cells

    PMID:23260140

    Open questions at the time
    • Chaperones or factors that specifically stabilize COX4I1 after import but before MITRAC integration are uncharacterized
    • Structural details of the COX4I1–MITRAC interaction interface are unknown
  5. 2017 High

    Identification of the first pathogenic COX4I1 mutation (K101N) in a patient with cytochrome c oxidase deficiency, rescued by wild-type complementation, established COX4I1 as a Mendelian disease gene for mitochondrial complex IV deficiency.

    Evidence Whole-exome sequencing, enzymatic and metabolic assays, lentiviral rescue in patient fibroblasts

    PMID:28766551

    Open questions at the time
    • Genotype–phenotype spectrum across additional COX4I1 variants is limited to very few patients
    • Mechanism by which K101N specifically destabilizes the protein (beyond loss of detectable COX4-1) is unresolved
  6. 2018 High

    The 3.3-Å cryo-EM structure of the human respiratory supercomplex I₁III₂IV₁ placed COX4I1 within the complete 14-subunit complex IV architecture and confirmed that functional complex IV is monomeric within the supercomplex.

    Evidence Cryo-EM of purified human mitochondrial supercomplex

    PMID:30030519

    Open questions at the time
    • How COX4-1 versus COX4-2 incorporation structurally alters the supercomplex interface is not resolved
    • Dynamic conformational changes of COX4I1 during the catalytic cycle are unknown
  7. 2020 Medium

    Discovery that Dynll1 forms a persistent complex with Cox4i1 and that pathogen-induced dissociation releases mitochondrial ROS to restrict intracellular Listeria revealed an unexpected innate-immune signaling role for complex IV subunit interactions.

    Evidence Mass spectrometry, co-immunoprecipitation, Listeria infection in dendritic cells, ROS measurement

    PMID:32041786

    Open questions at the time
    • Reciprocal validation (e.g., Cox4i1 bait pulling down Dynll1) and structural mapping of the interaction site are lacking
    • Whether this mechanism operates for other intracellular pathogens is unknown
    • How pathogen signals trigger dissociation of the Dynll1–Cox4i1 complex is unresolved
  8. 2021 High

    CRISPR knockout of COX4I1 demonstrated that its loss not only abolishes complex IV but secondarily impairs complex I biogenesis and mitochondrial translation, revealing an unexpected trans-complex dependency in OXPHOS assembly.

    Evidence CRISPR KO in HEK293, BN-PAGE complexome profiling, 35S pulse-chase metabolic labeling

    PMID:33578848

    Open questions at the time
    • Whether the complex I defect is caused by reduced mitoribosomal function or a specific assembly factor feedback is undefined
    • Applicability across tissues and in vivo models remains untested
  9. 2022 High

    Showing that COX4-1 expression drives supercomplex assembly and limits superoxide in glioblastoma cells, conferring radioresistance, linked respiratory chain structural organization to cancer therapy response and identified COX4-1 as a metabolic determinant of treatment sensitivity.

    Evidence Isogenic COX4-1 overexpression/silencing, BN-PAGE supercomplex analysis, Seahorse profiling, clonogenic radiation survival

    PMID:35478774

    Open questions at the time
    • Mechanism by which COX4-1 preferentially promotes supercomplex formation over COX4-2 is unknown
    • In vivo validation of supercomplex-dependent radioresistance is limited
  10. 2022 Medium

    Demonstrating that COX4-1-deficient cells accumulate replication-associated DNA damage, show impaired DNA damage response, and enter premature senescence extended COX4I1's role beyond bioenergetics to genome maintenance.

    Evidence Patient fibroblasts and siRNA knockdown, γH2AX immunofluorescence, genotoxin recovery, DDR gene expression

    PMID:35456968

    Open questions at the time
    • Whether the DNA damage phenotype is a direct consequence of elevated ROS or reduced nucleotide synthesis is unresolved
    • Single-lab observation awaiting independent confirmation
  11. 2024 High

    A CRISPR screen identifying COX4I1 as an AML vulnerability, with depletion inducing ferroptosis and synergizing with venetoclax, positioned COX4I1-dependent respiration as a druggable node in leukemia and mapped critical assembly-essential regions by gene tiling.

    Evidence CRISPR dropout screen, gene tiling, mitochondrial proteomics, in vivo AML xenograft, venetoclax synergy

    PMID:39716856

    Open questions at the time
    • Whether the ferroptosis phenotype is specific to AML or generalizable across hematologic malignancies is untested
    • Optimal therapeutic window for pharmacological COX4-1 inhibition has not been defined
  12. 2025 High

    Transmitochondrial cybrid reconstitution showed that COX4-1-containing mitochondria rewire redox metabolism—reducing labile iron and suppressing SLC7A11/GPX4—to divert cell death from ferroptosis toward apoptosis, separating mitochondrial from nuclear contributions to this effect.

    Evidence CRISPR POLG-KO ρ0 cells, cybrid reconstitution, CcO activity, cell death mode analysis, iron and cystine uptake assays

    PMID:41596099

    Open questions at the time
    • Signaling pathway linking COX4-1-dependent respiration to SLC7A11/GPX4 down-regulation is uncharacterized
    • Whether the ferroptosis–apoptosis switch is isoform-specific (COX4-1 vs. COX4-2) under matched conditions is not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis for differential supercomplex assembly by COX4-1 versus COX4-2, the signaling mechanism linking COX4I1 loss to impaired mitochondrial translation and complex I biogenesis, and whether pharmacological targeting of COX4-1-dependent respiration can be therapeutically exploited without on-target toxicity.
  • No isoform-resolved cryo-EM structure comparing COX4-1 and COX4-2 supercomplexes exists
  • Mechanism coupling COX4I1 deficiency to mitoribosomal protein depletion is undefined
  • Therapeutic index for COX4-1 pharmacological inhibition in cancer versus normal tissue is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 4 GO:0016491 oxidoreductase activity 4
Localization
GO:0005739 mitochondrion 5
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-1643685 Disease 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-5357801 Programmed Cell Death 2
Partners
COX4I2DYNLL1NDUFA4TIM21
Complex memberships
Cytochrome c oxidase (complex IV)MITRAC assembly intermediateRespiratory supercomplex I1III2IV1

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 HIF-1 reciprocally regulates COX4-1 and COX4-2 isoform expression in response to hypoxia: under low O2, HIF-1 activates transcription of COX4-2 and LON (a mitochondrial protease required for COX4-1 degradation), thereby switching subunit composition to optimize respiration efficiency. Manipulating COX4 isoform expression alters COX activity, ATP production, O2 consumption, and ROS generation. Transcriptional reporter assays, siRNA knockdown, overexpression, O2 consumption and ATP measurement, ROS assay Cell High 17418790
2007 Yeast Cox4 (ortholog of human COX4I1) binds Zn(II) via a single His and three conserved Cys residues; Cys-ligand substitutions abolish cytochrome oxidase assembly, demonstrating that Zn(II) binding is required for structural stability of the complex. NMR solution structure reveals a C-terminal globular domain with two β-sheets, the Zn buried within. NMR structure determination, site-directed mutagenesis of Zn-coordinating residues, yeast complementation / growth assays The Journal of biological chemistry High 17215247
2006 Translation of yeast COX4 is repressed in the absence of phosphatidylglycerol and cardiolipin (pgs1Δ mutant). A 50-nucleotide fragment with two stem-loops in the 5′-UTR acts as a cis-element inhibiting COX4 translation; a cytoplasmic protein factor specifically binds this element in pgs1Δ cells, linking mitochondrial lipid composition to nuclear-gene translational control. mtGFP reporter fusions, 5′-UTR deletion analysis, RNA-binding protein pulldown from cytoplasmic extracts, genetic complementation Molecular and cellular biology High 16428432
2009 Polyamines (spermidine) stimulate COX4 translation in yeast by promoting ribosome shunting over stem-loop (hairpin) structures in the COX4 mRNA 5′-UTR, identifying COX4 as the first member of the yeast 'polyamine modulon'. Polyamine-requiring spe1Δ mutant rescue, polysome profiling, 5′-UTR reporter assays The international journal of biochemistry & cell biology Medium 19695341
2017 A K101N missense mutation in human COX4I1 causes decreased COX activity, impaired ATP production, elevated ROS, and undetectable COX4-1 protein in patient fibroblasts; lentiviral transduction with wild-type COX4I1 restored COX activity and ATP production, establishing COX4I1 as the first nuclear-encoded subunit whose mutation causes human mitochondrial disease via COX deficiency. Whole-exome sequencing, Sanger confirmation, enzymatic activity assays, ATP measurement, ROS assay, lentiviral complementation European journal of human genetics High 28766551
2017 Chlorpromazine selectively inhibits cytochrome c oxidase (CcO) activity in chemoresistant glioma cells expressing COX4-1 but not in chemosensitive cells expressing COX4-2, and computer-docking shows tighter binding to COX4-1-containing CcO. COX4-1-expressing cells undergo selective cell-cycle arrest with chlorpromazine treatment in orthotopic mouse models. CcO enzymatic activity assays, in silico docking, cell cycle analysis, orthotopic mouse brain tumor model Oncotarget Medium 28455961
2021 Complete knockout of COX4I1 (COX4 subunit) in HEK293 cells abolishes complex IV (cIV) and causes profound deficiency of complex I (cI), reducing cI subunit levels and assembled cI. Pulse-chase metabolic labeling shows decreased mitochondrial translation of both cIV and cI subunits, and complexome profiling reveals accumulation of cI assembly intermediates, indicating that COX4I1 loss impairs mitochondrial protein synthesis and cI biogenesis. CRISPR/Cas9 knockout, BN-PAGE complexome profiling, pulse-chase 35S-metabolic labeling of mtDNA-encoded proteins, Western blotting of OXPHOS subunits Cells High 33578848
2020 Dynein light chain 1 (Dynll1) forms a persistent complex with mitochondrial Cox4i1; pathogen insult (Listeria monocytogenes) dissociates this complex, and dissociation is required for release of mitochondrial ROS that restrict intracellular bacterial proliferation. Thus Dynll1 acts as an inhibitor of mitochondrial ROS through its interaction with Cox4i1. Mass spectrometry of membrane proteins, co-immunoprecipitation, Listeria infection model in dendritic cells, ROS measurement Infection and immunity Medium 32041786
2022 COX4-1 expression promotes assembly of CcO-containing mitochondrial supercomplexes (SCs) in GBM cells and reduces superoxide production; overexpression of COX4-1 in radiosensitive cells is sufficient to shift metabolism from glycolytic to oxidative and confer radioresistance, while silencing in radioresistant cells disassembles SCs and increases superoxide. Isogenic GBM cell lines (COX4-1 OE / silencing), BN-PAGE for supercomplex analysis, Seahorse metabolic profiling, ROS measurement, clonogenic radiation survival assay Cell stress High 35478774
2018 HIF-1α regulates the COXIV-1/COXIV-2 ratio in neurons following microwave-induced mitochondrial ROS production: HIF-1α inhibition down-regulates COX4I1 expression, impairs mitochondrial membrane potential and ATP production, and increases ROS, indicating HIF-1α maintains COX4I1 levels as a protective response. In vivo microwave exposure model, HIF-1α inhibitor treatment, luciferase reporter for HIF-1α transcriptional activity, Western blot, ATP and ROS measurement, MMP assay Scientific reports Medium 29991768
2021 miR-338 directly targets COX4I1; inhibition of miR-338 increases COX4I1 protein and CcO activity, improving ATP production and cell survival after ischemia/glucose deprivation in astrocytes and neurons. Concurrent siRNA knockdown of COX4I1 abolishes the protective effect, placing COX4I1 downstream of miR-338 in the ischemic injury pathway. miR-338 antagomir/mimic in vivo (MCAO model) and in vitro, CcO activity assay, ATP measurement, siRNA epistasis experiment, infarct size measurement Mitochondrion High 33933660
2024 COX4I1 depletion in EVT trophoblast cells inhibits proliferation, increases migration and invasion, impairs mitochondrial respiration and glycolysis, and promotes mitochondrial fusion; MMP1 knockdown rescues the increased migration/invasion caused by COX4I1 silencing, placing MMP1 downstream of COX4I1 in trophoblast invasion control. siRNA knockdown, RTCA proliferation/migration/invasion assay, EdU, MitoTracker staining, Seahorse metabolic analysis, siRNA epistasis (MMP1) Placenta Medium 38718733
2022 COX4-1 deficiency leads to replicative stress and impaired nuclear DNA damage response: patient fibroblasts and COX4I1-knockdown cells accumulate DNA damage preferentially in proliferating cells, show reduced DNA damage response pathway expression, impaired recovery from genotoxic insult, and decreased DNA repair capacity, leading to premature senescence. Patient fibroblasts (COX4I1 mutation), siRNA knockdown, γH2AX immunofluorescence, DNA damage response gene expression, genotoxin recovery assay International journal of molecular sciences Medium 35456968
2024 CRISPR screen identified COX4I1 as a vulnerability in AML; COX4I1 depletion induces mitochondrial stress and ferroptosis, disrupts mitochondrial ultrastructure and OXPHOS, and synergizes with venetoclax. CRISPR tiling scans coupled with mitochondrial proteomics identified critical regions within COX4I1 essential for complex IV assembly. Cell signaling-focused CRISPR screen, COX4I1 KO/depletion, mitochondrial proteomics, CRISPR gene tiling, in vivo AML xenograft, drug synergy assay (venetoclax + chlorpromazine) Advanced science High 39716856
2018 Human cytochrome c oxidase complex IV contains 14 subunits; cryo-EM structure at 3.3 Å of the human supercomplex I1III2IV1 assigned NDUFA4 as a subunit of complex IV occupying the dimeric interface, demonstrating that the intact complex IV is a monomer. COX4I1 (subunit IV-1) is resolved as part of the complete structure. Cryo-EM structure determination at 3.3 Å from human supercomplex Cell research High 30030519
2012 COX4I1 (as an early-assembling, presequence-containing subunit) is integrated into cytochrome c oxidase assembly intermediates (MITRAC complexes) via TIM21, which links the TIM23 mitochondrial presequence translocase to respiratory-chain assembly; loss of TIM21 impairs integration of COX4I1-containing subunits into assembly intermediates and regulates mitochondrial protein synthesis in response to assembly state. Comprehensive co-IP/AP-MS of COX assembly intermediates, TIM21 knockdown, pulse-chase metabolic labeling, BN-PAGE Cell High 23260140
2025 Arachidonoyl-phosphatidylethanolamine (AA-PE), accumulated in brown adipose tissue mitochondria during cold stress via LPCAT3, partitions at the COX4I1 interface of cytochrome c oxidase; lipid-based proteomics, MD simulations, and bioenergetic analyses show this interaction enhances electron transport chain efficiency and is required for respiratory-dependent thermogenesis. Lipid-based proteomics, molecular dynamics simulations, bioenergetic (ETC) analysis, fat-specific Lpcat3-KO mice, cold acclimation model bioRxivpreprint Medium bio_10.1101_2025.05.15.654206
2025 COX4I1-expressing (transmitochondrial) cybrid cells reconstituted with COX4-1-containing mitochondria restore CcO activity and confer resistance to erastin-induced ferroptosis, instead undergoing apoptosis; COX4-1 cybrids exhibit reduced labile iron, diminished cystine uptake, and low SLC7A11/GPX4 expression, demonstrating that mitochondrial COX4-1 rewires redox metabolism and diverts cell-death signaling from ferroptosis to apoptosis. CRISPR POLG-KO ρ0 cells, transmitochondrial cybrid reconstitution, CcO activity assay, cell death mode analysis, iron measurement, cystine uptake, Western blot for SLC7A11/GPX4 Antioxidants High 41596099
2011 Cytochrome c oxidase (COX) activity and COX4 protein levels are regulated by reversible phosphorylation downstream of cAMP/PKA and tyrosine kinase signaling, linking cell signaling pathways to COX activity, mitochondrial membrane potential, and ROS/ATP production; identified phosphorylation sites on COX subunits including COX4I1. Phosphoproteomic analysis of COX, kinase/signaling inhibitor studies, crystal-structure mapping of phosphorylation sites Biochimica et biophysica acta Medium 21771582
2025 A de novo nonsense COX4I1 variant in trans with a deep intronic variant (causing frameshift) primarily reduces COX4I1 protein levels, impairing complex IV assembly and activity. Proteomic analysis of patient fibroblasts also revealed decreased levels of mitoribosomal proteins, suggesting COX4I1 deficiency secondarily affects mitochondrial ribosome homeostasis. Short- and long-read NGS, functional studies in patient tissues and transfected cell lines, complex IV activity assay, mitochondrial proteomics Mitochondrion Medium 41203052

Source papers

Stage 0 corpus · 63 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2007 HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell 996 17418790
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2011 Global landscape of HIV-human protein complexes. Nature 593 22190034
2017 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science (New York, N.Y.) 533 28302793
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2011 Defining human ERAD networks through an integrative mapping strategy. Nature cell biology 427 22119785
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2016 Identification of Zika Virus and Dengue Virus Dependency Factors using Functional Genomics. Cell reports 306 27342126
2019 Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality. Cancer cell 298 31056398
2020 Virus-Host Interactome and Proteomic Survey Reveal Potential Virulence Factors Influencing SARS-CoV-2 Pathogenesis. Med (New York, N.Y.) 291 32838362
2004 Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation. Nature biotechnology 266 15146197
2022 CST1 inhibits ferroptosis and promotes gastric cancer metastasis by regulating GPX4 protein stability via OTUB1. Oncogene 259 36369321
2021 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. Cell metabolism 239 34800366
2011 Regulation of mitochondrial respiration and apoptosis through cell signaling: cytochrome c oxidase and cytochrome c in ischemia/reperfusion injury and inflammation. Biochimica et biophysica acta 223 21771582
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2012 MITRAC links mitochondrial protein translocation to respiratory-chain assembly and translational regulation. Cell 196 23260140
2018 Structure of the intact 14-subunit human cytochrome c oxidase. Cell research 175 30030519
2014 Global mapping of herpesvirus-host protein complexes reveals a transcription strategy for late genes. Molecular cell 173 25544563
2019 A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape. Nature immunology 159 30833792
2017 Repositioning chlorpromazine for treating chemoresistant glioma through the inhibition of cytochrome c oxidase bearing the COX4-1 regulatory subunit. Oncotarget 63 28455961
2015 Male obesity is associated with changed spermatozoa Cox4i1 mRNA level and altered seminal vesicle fluid composition in a mouse model. Molecular human reproduction 60 25731709
2017 Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia. European journal of human genetics : EJHG 47 28766551
2021 Loss of COX4I1 Leads to Combined Respiratory Chain Deficiency and Impaired Mitochondrial Protein Synthesis. Cells 43 33578848
1990 Isolation and characterization of QCR9, a nuclear gene encoding the 7.3-kDa subunit 9 of the Saccharomyces cerevisiae ubiquinol-cytochrome c oxidoreductase complex. An intron-containing gene with a conserved sequence occurring in the intron of COX4. The Journal of biological chemistry 43 2174427
2008 Noncovalent interactions under extreme conditions: high-pressure and low-temperature diffraction studies of the isostructural metal-organic networks (4-chloropyridinium)2[CoX4] (X = Cl, Br). Journal of the American Chemical Society 39 18564841
2007 The characterization and role of zinc binding in yeast Cox4. The Journal of biological chemistry 32 17215247
2020 Cytochrome C Oxidase Subunit 4 (COX4): A Potential Therapeutic Target for the Treatment of Medullary Thyroid Cancer. Cancers 26 32911610
2006 Translational regulation of nuclear gene COX4 expression by mitochondrial content of phosphatidylglycerol and cardiolipin in Saccharomyces cerevisiae. Molecular and cellular biology 25 16428432
2009 Polyamine modulon in yeast-Stimulation of COX4 synthesis by spermidine at the level of translation. The international journal of biochemistry & cell biology 24 19695341
2018 HIF-1α regulates COXIV subunits, a potential mechanism of self-protective response to microwave induced mitochondrial damages in neurons. Scientific reports 23 29991768
2019 Biallelic variants in COX4I1 associated with a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures. American journal of medical genetics. Part A 20 31290619
1987 The untranslated leader of nuclear COX4 gene of Saccharomyces cerevisiae contains an intron. Nucleic acids research 20 3033605
2022 COX4-1 promotes mitochondrial supercomplex assembly and limits reactive oxide species production in radioresistant GBM. Cell stress 19 35478774
2020 COXIV and SIRT2-mediated G6PD deacetylation modulate ROS homeostasis to extend pupal lifespan. The FEBS journal 17 33058529
2020 The Dynll1-Cox4i1 Complex Regulates Intracellular Pathogen Clearance via Release of Mitochondrial Reactive Oxygen Species. Infection and immunity 16 32041786
1999 The 5' region of the COX4 gene contains a novel overlapping gene, NOC4. Mammalian genome : official journal of the International Mammalian Genome Society 15 10337626
2021 MicroRNA-338 inhibition protects against focal cerebral ischemia and preserves mitochondrial function in vitro in astrocytes and neurons via COX4I1. Mitochondrion 14 33933660
2010 The cardiac copper chaperone proteins Sco1 and CCS are up-regulated, but Cox 1 and Cox4 are down-regulated, by copper deficiency. Biological trace element research 14 20878365
2024 Cytochrome c oxidase IV isoform 1 (COX4-1) regulates the proliferation, migration and invasion of trophoblast cells via modulating mitochondrial function. Placenta 12 38718733
2022 Replicative Stress Coincides with Impaired Nuclear DNA Damage Response in COX4-1 Deficiency. International journal of molecular sciences 10 35456968
2022 COX4-like, a Nuclear-Encoded Mitochondrial Gene Duplicate, Is Essential for Male Fertility in Drosophila melanogaster. Genes 9 35327978
2017 Subfunctionalization of COX4 paralogs in fish. American journal of physiology. Regulatory, integrative and comparative physiology 9 28148493
2007 Leptin stimulation of COXIV is impaired in obese skeletal muscle myotubes. Obesity research & clinical practice 8 24351431
2022 Destabilizing COXIV in Müller Glia Increases Retinal Glycolysis and Alters Scotopic Electroretinogram. Cells 7 36497016
2024 Nuclear Control of Mitochondrial Homeostasis and Venetoclax Efficacy in AML via COX4I1. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 6 39716856
2018 Comparison of Pre- and Post-translational Expressions of COXIV-1 and MT-ATPase 6 Genes in Colorectal Adenoma-Carcinoma Tissues. Journal of carcinogenesis & mutagenesis 6 30393577
2016 Evaluating the role of NRF-1 in the regulation of the goldfish COX4-1 gene in response to temperature. The Journal of experimental biology 6 27471277
2025 Compound heterozygosity of a De novo 16q24.1 deletion and missense mutation in COX4I1 leads to developmental regression, intellectual disability, and seizures. Epilepsia open 2 40095452
2002 Cloning of COX4 cDNA from the NZ white rabbit and expression of this gene in bladder smooth muscle following partial outlet obstruction. World journal of urology 2 12215857
2025 The Nuclear-Encoded Cytochrome c Oxidase Subunit COX4-1 Enhances Hypoxia Tolerance in Glioblastoma Cells. Journal of oncology research and therapy 1 40958887
2025 Complex IV deficiency due to COX4I1 deep intronic and de novo variants results in progressive motor impairment and Leigh syndrome. Mitochondrion 1 41203052
2025 Cytochrome c Oxidase Subunit COX4-1 Reprograms Erastin-Induced Cell Death from Ferroptosis to Apoptosis: A Transmitochondrial Study. Antioxidants (Basel, Switzerland) 0 41596099