Affinage

COX5B

Cytochrome c oxidase subunit 5B, mitochondrial · UniProt P10606

Length
129 aa
Mass
13.7 kDa
Annotated
2026-06-09
14 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

COX5B is a structural subunit of cytochrome c oxidase (Complex IV) whose loss produces mitochondrial dysfunction—elevated ROS, depolarized membrane potential, and diminished ATP—coupled to metabolic reprogramming, cellular senescence, and suppressed proliferation across breast cancer, hepatoma, and Leydig cells (PMID:26506233, PMID:39586785). Its expression is set by upstream regulators that converge on mitochondrial bioenergetics: in cancer it acts as a downstream effector of NDUFS4 in glioma and of MZT2B in NSCLC, where restoring COX5B rescues the anti-tumor phenotypes of depleting these regulators (PMID:41213905, PMID:41617910), and it drives malignant proliferation and migration through bioenergetic activation of an AMPK–UHMK1–ERK/stathmin axis and through control of the tight-junction effector CLDN2 that modulates drug susceptibility (PMID:32580279, PMID:35052740). COX5B mRNA stability and translation are positively controlled by YBX1, which binds TRDMT1-deposited m5C marks on COX5B transcripts via a defined LYS-92/C-153 interface to reduce ROS and improve mitochondrial function under oxidative stress (PMID:40253045). Beyond its respiratory role, COX5B physically binds MAVS at mitochondria and negatively regulates antiviral signaling by repressing MAVS-driven ROS and coordinating with ATG5-dependent autophagy to limit MAVS aggregation (PMID:23308066). In yeast, COX5b transcription is governed by discrete cis-acting elements (activating sequences UAS1/UAS2, the URS5b repression sequence, and a TATA region) mediating carbon-source control and aerobic repression, with REO1 acting as a trans-acting aerobic repressor genetically upstream of COX5b (PMID:2169024, PMID:2852136).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1988 High

    Established that COX5b expression is under trans-acting negative control during aerobiosis, defining a regulatory node controlling respiratory subunit production by oxygen availability.

    Evidence genetic suppressor screen, complementation, and epistasis in yeast

    PMID:2852136

    Open questions at the time
    • Molecular identity and biochemical mechanism of REO1 repression not resolved
    • Does not address mammalian regulation
  2. 1990 High

    Mapped the cis-regulatory architecture of COX5b, separating carbon-source activation from aerobic repression into discrete promoter elements.

    Evidence deletion mapping with reporter assays in yeast

    PMID:2169024

    Open questions at the time
    • Trans-acting factors binding each element not all identified
    • No link to protein-level function
  3. 2012 High

    Revealed a moonlighting role for COX5B beyond respiration: it dampens antiviral innate immunity by binding MAVS and restraining ROS and MAVS aggregation via autophagy.

    Evidence reciprocal Co-IP, ROS and autophagy assays, loss-of-function in mammalian cells

    PMID:23308066

    Open questions at the time
    • Structural basis of the COX5B–MAVS interaction unknown
    • Mechanistic link between Complex IV function and MAVS regulation unresolved
  4. 2015 Medium

    Demonstrated that COX5B is required for Complex IV-dependent mitochondrial respiration, with its loss triggering metabolic reprogramming and senescence in cancer cells.

    Evidence siRNA knockdown with SILAC, ROS, MMP, ATP, proliferation and senescence assays in breast cancer cells

    PMID:26506233

    Open questions at the time
    • Single lab and cell context
    • Does not define how bioenergetic loss signals to senescence machinery
  5. 2020 Medium

    Connected COX5B bioenergetic activity to an oncogenic signaling cascade, identifying AMPK–UHMK1–ERK/stathmin as the downstream effector axis in hepatoma.

    Evidence loss/gain-of-function, microarray, phosphoproteomics, xenografts

    PMID:32580279

    Open questions at the time
    • Single tumor type
    • Direct biochemical coupling between Complex IV output and AMPK activation not shown
  6. 2021 Medium

    Extended COX5B's oncogenic output to drug resistance, identifying CLDN2 as a bioenergetics-dependent effector in colorectal cancer.

    Evidence COX5B silencing, RNA-seq, RT-qPCR, CLDN2 compensation experiments

    PMID:35052740

    Open questions at the time
    • Mechanism linking metabolism to CLDN2 transcription unknown
    • Single lab
  7. 2024 Medium

    Confirmed COX5B as a general requirement for Complex IV activity and mitochondrial health, generalizing the respiratory/senescence phenotype to testicular Leydig cells.

    Evidence siRNA knockdown with ROS, ATP, MMP, senescence and proliferation assays in TM3 cells

    PMID:39586785

    Open questions at the time
    • No new mechanism beyond confirming respiratory role
    • Single cell line
  8. 2025 Medium

    Identified post-transcriptional control of COX5B, showing YBX1 reads TRDMT1-deposited m5C marks to stabilize and translate COX5B mRNA and protect mitochondria from oxidative stress.

    Evidence m5C assays, mutagenesis of the YBX1 LYS-92/COX5B C-153 interface, exosome co-culture, ROS and mitochondrial assays in granulosa cells

    PMID:40253045

    Open questions at the time
    • Generalizability of m5C regulation to other cell types untested
    • Physiological trigger for TRDMT1 methylation unknown
  9. 2025 Medium

    Established COX5B as a downstream effector of MZT2B, placing COX5B in an upstream-regulator hierarchy controlling NSCLC bioenergetics and tumor phenotypes.

    Evidence shRNA/CRISPR knockout of MZT2B, COX5B rescue, OCR measurement, xenografts

    PMID:41213905

    Open questions at the time
    • Mechanism by which MZT2B regulates COX5B expression unknown
    • Single lab
  10. 2025 Medium

    Defined a conserved antiviral/autophagy role in insects, where COX5B redirects a viral protein to mitochondria, sustains Atg3-dependent autophagosome maturation, and suppresses PI3K-Akt to promote apoptosis.

    Evidence Co-IP with viral P5-2, RNAi, TEM of autophagosomes, PI3K-Akt analysis in Sogatella furcifera

    PMID:41358576

    Open questions at the time
    • Conservation of this mechanism in mammals not tested
    • Direct structural basis of P5-2 binding unresolved
  11. 2026 Medium

    Identified COX5B as a downstream effector of NDUFS4, linking Complex I regulation to COX5B-dependent mitochondrial function and glioma growth.

    Evidence shRNA/CRISPR knockout of NDUFS4, COX5B silencing/rescue, OCR, Complex I assay, intracranial xenografts

    PMID:41617910

    Open questions at the time
    • Mechanism by which NDUFS4 controls COX5B expression unknown
    • Cross-talk between Complex I and Complex IV subunit levels unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How COX5B mechanistically couples Complex IV bioenergetic output to its diverse downstream signaling roles (AMPK, CLDN2, MAVS, apoptosis) and how its upstream regulators (NDUFS4, MZT2B) control its expression remain unresolved.
  • No structural model of COX5B within Complex IV or with non-respiratory partners
  • Direct biochemical link between respiratory function and signaling cascades undefined
  • Mammalian relevance of insect antiviral mechanism untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2
Localization
GO:0005739 mitochondrion 3
Pathway
R-HSA-1430728 Metabolism 2 R-HSA-168256 Immune System 1
Partners
MAVSTRDMT1YBX1
Complex memberships
cytochrome c oxidase (Complex IV)

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 COX5B physically interacts with MAVS at mitochondria and negatively regulates MAVS-mediated antiviral signaling; mechanistically, COX5B represses ROS production downstream of MAVS activation, and coordinates with the autophagy pathway (via ATG5) to control MAVS aggregation, thereby dampening antiviral signaling activity. Co-immunoprecipitation, ROS measurement, autophagy pathway analysis, loss-of-function experiments in mammalian cells PLoS pathogens High 23308066
2015 Loss of COX5B in breast cancer cells induces mitochondrial dysfunction (increased ROS, depolarized mitochondrial membrane potential, decreased ATP), metabolic reprogramming (increased glucose uptake, decreased lactate secretion), and consequently suppresses cell proliferation and induces cellular senescence. siRNA knockdown of COX5B, SILAC assay, ROS measurement, MMP assay, ATP quantification, proliferation and senescence assays Oncotarget Medium 26506233
1990 Transcription of yeast COX5b is controlled by at least four distinct cis-acting regulatory elements upstream of the transcriptional start: two upstream activating sequences (UAS1(5b) and UAS2(5b)), one upstream repression sequence (URS5b), and a TATA region; UAS1(5b) mediates carbon source control and URS5b mediates aerobic repression. Deletion analysis of upstream regulatory region, reporter gene assays with heterologous yeast genes Molecular and cellular biology High 2169024
1988 In yeast, REO1 is a trans-acting negative regulator of COX5b expression under aerobic conditions; recessive reo1 mutations increase COX5b expression in aerobically grown cells but not anaerobically, and their phenotypic effect requires a functional COX5b gene, placing REO1 upstream of COX5b in the aerobic repression pathway. Genetic screen for suppressor mutations, complementation analysis, epistasis (reo1 phenotype requires COX5b), growth assays on non-fermentable carbon sources Genetics High 2852136
2020 COX5B drives hepatoma cell proliferation and migration through bioenergetic alteration-dependent activation of AMPK, which upregulates the oncogenic kinase UHMK1, which in turn activates ERK- and stathmin-mediated downstream pathways. Loss- and gain-of-function experiments, cDNA microarray, phosphoproteomic analysis, xenograft tumor growth assays Cancers Medium 32580279
2021 COX5B promotes colorectal cancer cell growth and attenuates anticancer drug susceptibility by orchestrating expression of the tight junction protein Claudin-2 (CLDN2) downstream of COX5B-mediated bioenergetic alterations; CLDN2 was identified as the downstream effector by RNA sequencing and validated by functional compensation experiments. COX5B silencing, RNA sequencing, RT-qPCR, functional compensation experiments with CLDN2 re-expression Biomedicines Medium 35052740
2025 YBX1 (delivered via HuMSC-derived exosomes) binds to m5C-modified COX5B mRNA (methylated by TRDMT1) through its LYS-92 residue interacting with COX5B C-153, stabilizing COX5B mRNA and promoting COX5B translation, which reduces ROS and improves mitochondrial function in granulosa cells under oxidative stress. m5C RNA methylation assays, mutational analysis of YBX1-COX5B mRNA interaction (LYS-92), exosome co-culture experiments, ROS and mitochondrial function assays International journal of biological macromolecules Medium 40253045
2024 Knockdown of COX5B in TM3 cells (Leydig cells) causes mitochondrial dysfunction (increased ROS, decreased ATP, reduced mitochondrial membrane potential), aggravates cellular senescence, and reduces cell proliferation, establishing COX5B as a functional component required for normal mitochondrial respiratory chain complex IV activity in testicular cells. COX5B knockdown via siRNA in TM3 cells, ROS measurement, ATP quantification, MMP assay, senescence assay, proliferation assay Journal of cellular and molecular medicine Medium 39586785
2025 In insect cells (Sogatella furcifera), COX5B directly interacts with viral protein P5-2, redirecting it to mitochondria and counteracting its autophagy-suppressive effects by sustaining Atg3-mediated autophagosome maturation; COX5B upregulation also suppresses PI3K-Akt signaling to promote apoptosis in severely virus-infected cells. Co-immunoprecipitation of COX5B with P5-2, RNAi knockdown of COX5B, transmission electron microscopy of autophagosomes, PI3K-Akt pathway analysis Autophagy Medium 41358576
2025 MZT2B (mitotic spindle organizing protein 2B) positively regulates COX5B expression in NSCLC cells; COX5B acts as a downstream effector of MZT2B, as restoring COX5B expression in MZT2B-depleted cells abrogates anti-tumor effects on proliferation, migration, invasion, and mitochondrial function. shRNA and CRISPR/Cas9 knockout of MZT2B, COX5B rescue/overexpression experiments, oxygen consumption rate measurement, xenograft in vivo model Cell death & disease Medium 41213905
2026 NDUFS4 (mitochondrial complex I subunit) positively regulates COX5B expression in glioma cells; COX5B is a downstream effector of NDUFS4, as shRNA silencing of COX5B recapitulates NDUFS4 depletion phenotypes and COX5B restoration in NDUFS4-silenced cells abrogates anti-glioma effects including mitochondrial dysfunction, reduced proliferation, and apoptosis. shRNA knockdown and CRISPR/Cas9 knockout of NDUFS4, COX5B silencing and rescue experiments, oxygen consumption rate, mitochondrial complex I activity assay, intracranial xenograft model NPJ precision oncology Medium 41617910

Source papers

Stage 0 corpus · 14 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 COX5B regulates MAVS-mediated antiviral signaling through interaction with ATG5 and repressing ROS production. PLoS pathogens 109 23308066
2015 Loss of COX5B inhibits proliferation and promotes senescence via mitochondrial dysfunction in breast cancer. Oncotarget 37 26506233
1990 Upstream activation and repression elements control transcription of the yeast COX5b gene. Molecular and cellular biology 29 2169024
1988 Identification of REO1, a gene involved in negative regulation of COX5b and ANB1 in aerobically grown Saccharomyces cerevisiae. Genetics 28 2852136
2020 COX5B-Mediated Bioenergetic Alteration Regulates Tumor Growth and Migration by Modulating AMPK-UHMK1-ERK Cascade in Hepatoma. Cancers 24 32580279
2017 Decreased Tissue COX5B Expression and Mitochondrial Dysfunction during Sepsis-Induced Kidney Injury in Rats. Oxidative medicine and cellular longevity 20 28246552
2017 Identification of COX5B as a novel biomarker in high-grade glioma patients. OncoTargets and therapy 18 29180880
2021 COX5B-Mediated Bioenergetic Alterations Modulate Cell Growth and Anticancer Drug Susceptibility by Orchestrating Claudin-2 Expression in Colorectal Cancers. Biomedicines 13 35052740
2025 HuMSCs-derived exosomal YBX1 participates in oxidative damage repair in granulosa cells by stabilizing COX5B mRNA in an m5C-dependent manner. International journal of biological macromolecules 9 40253045
2024 Abnormal Expression of COX5B Gene and Disorder of Mitochondrial Function in Cryptorchid Rats. Journal of cellular and molecular medicine 4 39586785
2026 Mitochondrial complex I subunit NDUFS4 overexpression drives glioma progression by regulating mitochondrial function and COX5B. NPJ precision oncology 0 41617910
2025 MZT2B promotes malignant phenotypes in NSCLC cells by enhancing mitochondrial function and COX5B expression. Cell death & disease 0 41213905
2025 Mitochondrial protein COX5B orchestrates antiviral autophagy and apoptosis to restrict SRBSDV propagation in Sogatella furcifera. Autophagy 0 41358576
2025 Integrative Multi-Omics Analysis and Experiments Validation Identify COX5B as a Novel Therapeutic Target for Lung Adenocarcinoma. Oncology research 0 41502520

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