Cytochrome c oxidase subunit 6A1 (COX6A1) is the liver-type nuclear-encoded COX6A isoform and a supernumerary subunit of mitochondrial Complex IV. It is a single-pass inner mitochondrial membrane component of mature cytochrome c oxidase, with a structural/regulatory role rather than an independent redox catalytic activity. COX6A1 contributes to Complex IV-dependent electron transport and oxidative phosphorylation as part of the intact enzyme, and pathogenic variants cause recessive intermediate Charcot-Marie-Tooth disease with Complex IV dysfunction.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006123 mitochondrial electron transport, cytochrome c to oxygen | IBA GO_REF:0000033 | ACCEPT | Summary: COX6A1 participates in mitochondrial electron transport from cytochrome c to oxygen as a bona fide subunit of Complex IV. The electron-transfer chemistry is executed by the intact enzyme, especially MT-CO1 and MT-CO2, but COX6A1 is part of the functional holoenzyme. Reason: Correct Complex IV biological-process annotation for a structural/regulatory subunit. Supporting Evidence: file:human/COX6A1/COX6A1-deep-research-falcon.md Cytochrome c oxidase (COX; Complex IV) is the **terminal enzyme of the mitochondrial electron transport chain**, catalyzing electron transfer to oxygen and contributing to the proton gradient that powers ATP synthesis in oxidative phosphorylation (OXPHOS). |
| GO:0045277 respiratory chain complex IV | IBA GO_REF:0000033 | ACCEPT | Summary: Structural work on human cytochrome c oxidase includes COX6A1 among the 14 subunits of the intact Complex IV monomer. Reason: Core complex-membership annotation. Supporting Evidence: file:human/COX6A1/COX6A1-deep-research-falcon.md High-resolution cryo-EM of **intact human CIV (14-subunit monomer)** resolved COX6A1 as one of the assigned subunits and showed that, compared with bovine heart CIV dimer structures, **human COX6A1 replaces bovine COX6A2** |
| GO:0030234 enzyme regulator activity | IBA GO_REF:0000033 | ACCEPT | Summary: COX6A family members are regulatory/supernumerary Complex IV subunits. The enzyme-regulator annotation captures the non-catalytic modulatory role better than assigning cytochrome-c oxidase activity directly to COX6A1. Reason: Appropriate molecular-function-level representation for a regulatory Complex IV subunit. Supporting Evidence: file:human/COX6A1/COX6A1-deep-research-falcon.md Reviews emphasize that these nuclear-encoded subunits (including COX6A) are generally **not the catalytic center** but **modulate COX activity and/or stability/assembly**. file:human/COX6A1/COX6A1-deep-research-falcon.md Evidence summarized in reviews indicates COX6A isoforms can influence proton pumping efficiency and allosteric regulation of cytochrome c oxidase, while COX6A also contacts the opposite protomer in dimeric models and is proposed to stabilize quaternary structure. |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000120 | ACCEPT | Summary: COX6A1 is a single-pass mitochondrial inner membrane subunit of Complex IV. Reason: Correct core localization. Supporting Evidence: file:human/COX6A1/COX6A1-deep-research-falcon.md COX6A1 is a mitochondrial complex IV subunit embedded in the inner mitochondrial membrane context of cytochrome c oxidase/respirasome assemblies. |
| GO:0005515 protein binding | IPI PMID:17500595 Huntingtin interacting proteins are genetic modifiers of neu... | MARK AS OVER ANNOTATED | Summary: The protein-binding annotations derive from interaction screens or disease-network interactomes and do not specify the mechanistic role of COX6A1 in Complex IV. Reason: Generic protein binding is uninformative for this subunit and is better represented by Complex IV membership and regulatory subunit activity. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: The protein-binding annotations derive from interaction screens or disease-network interactomes and do not specify the mechanistic role of COX6A1 in Complex IV. Reason: Generic protein binding is uninformative for this subunit and is better represented by Complex IV membership and regulatory subunit activity. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: The protein-binding annotations derive from interaction screens or disease-network interactomes and do not specify the mechanistic role of COX6A1 in Complex IV. Reason: Generic protein binding is uninformative for this subunit and is better represented by Complex IV membership and regulatory subunit activity. |
| GO:0006119 oxidative phosphorylation | IEA GO_REF:0000041 | KEEP AS NON CORE | Summary: COX6A1 participates in oxidative phosphorylation through its role in Complex IV. The term is correct but broad. Reason: Keep as non-core because the more precise Complex IV electron-transport annotation better captures the gene product role. Supporting Evidence: file:human/COX6A1/COX6A1-deep-research-falcon.md COX6A1 functions within complex IV of the oxidative phosphorylation system, the terminal respiratory-chain complex that transfers electrons to oxygen and helps generate the proton gradient for ATP synthesis. |
| GO:0006123 mitochondrial electron transport, cytochrome c to oxygen | NAS PMID:30030519 Structure of the intact 14-subunit human cytochrome c oxidas... | ACCEPT | Summary: COX6A1 participates in mitochondrial electron transport from cytochrome c to oxygen as a bona fide subunit of Complex IV. The electron-transfer chemistry is executed by the intact enzyme, especially MT-CO1 and MT-CO2, but COX6A1 is part of the functional holoenzyme. Reason: Correct Complex IV biological-process annotation for a structural/regulatory subunit. Supporting Evidence: PMID:30030519 CIV is the terminal oxidase of the electron transport chain in mitochondria. file:human/COX6A1/COX6A1-deep-research-falcon.md Cytochrome c oxidase (COX; Complex IV) is the **terminal enzyme of the mitochondrial electron transport chain**, catalyzing electron transfer to oxygen and contributing to the proton gradient that powers ATP synthesis in oxidative phosphorylation (OXPHOS). |
| GO:0031966 mitochondrial membrane | IDA PMID:30030519 Structure of the intact 14-subunit human cytochrome c oxidas... | ACCEPT | Summary: Mitochondrial membrane is a correct broader localization supported by the ComplexPortal structural annotation. Reason: Accept as correct but less specific than mitochondrial inner membrane. Supporting Evidence: PMID:30030519 Current opinions point out that CIV exists in two states under physiological conditions, either being assembled into supercomplexes or freely scattered on mitochondrial inner membrane. file:human/COX6A1/COX6A1-deep-research-falcon.md COX6A1 is a mitochondrial complex IV subunit embedded in the inner mitochondrial membrane context of cytochrome c oxidase/respirasome assemblies. |
| GO:0045277 respiratory chain complex IV | IPI PMID:30030519 Structure of the intact 14-subunit human cytochrome c oxidas... | ACCEPT | Summary: Structural work on human cytochrome c oxidase includes COX6A1 among the 14 subunits of the intact Complex IV monomer. Reason: Core complex-membership annotation. Supporting Evidence: PMID:30030519 we obtained the entire CIV structure containing 14 subunits, which includes the extra subunit NDUFA4 file:human/COX6A1/COX6A1-deep-research-falcon.md High-resolution cryo-EM of **intact human CIV (14-subunit monomer)** resolved COX6A1 as one of the assigned subunits and showed that, compared with bovine heart CIV dimer structures, **human COX6A1 replaces bovine COX6A2** |
| GO:0045333 cellular respiration | NAS PMID:30030519 Structure of the intact 14-subunit human cytochrome c oxidas... | KEEP AS NON CORE | Summary: Cellular respiration is correct at the pathway level for a Complex IV subunit, but it is broad relative to the specific mitochondrial electron-transport process. Reason: Keep as non-core. Supporting Evidence: file:human/COX6A1/COX6A1-deep-research-falcon.md COX6A1 functions within complex IV of the oxidative phosphorylation system, the terminal respiratory-chain complex that transfers electrons to oxygen and helps generate the proton gradient for ATP synthesis. |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: COX6A1 is a mitochondrial Complex IV subunit. Reason: Correct broad localization; the inner membrane annotation is more precise. Supporting Evidence: file:human/COX6A1/COX6A1-deep-research-falcon.md COX6A1 is a mitochondrial complex IV subunit embedded in the inner mitochondrial membrane context of cytochrome c oxidase/respirasome assemblies. |
| GO:0005743 mitochondrial inner membrane | EXP PMID:30030519 Structure of the intact 14-subunit human cytochrome c oxidas... | ACCEPT | Summary: COX6A1 is a single-pass mitochondrial inner membrane subunit of Complex IV. Reason: Correct core localization. Supporting Evidence: PMID:30030519 Current opinions point out that CIV exists in two states under physiological conditions, either being assembled into supercomplexes or freely scattered on mitochondrial inner membrane. file:human/COX6A1/COX6A1-deep-research-falcon.md COX6A1 is a mitochondrial complex IV subunit embedded in the inner mitochondrial membrane context of cytochrome c oxidase/respirasome assemblies. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: COX6A1 is a mitochondrial Complex IV subunit. Reason: Correct broad localization; the inner membrane annotation is more precise. Supporting Evidence: file:human/COX6A1/COX6A1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion file:human/COX6A1/COX6A1-deep-research-falcon.md Structural data place COX6A1 within human CIV purified from mitochondrial supercomplexes, supporting mitochondrial localization at the respiratory chain. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-163214 | ACCEPT | Summary: COX6A1 is a single-pass mitochondrial inner membrane subunit of Complex IV. Reason: Correct core localization. Supporting Evidence: file:human/COX6A1/COX6A1-deep-research-falcon.md COX6A1 is a mitochondrial complex IV subunit embedded in the inner mitochondrial membrane context of cytochrome c oxidase/respirasome assemblies. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9709406 | ACCEPT | Summary: COX6A1 is a single-pass mitochondrial inner membrane subunit of Complex IV. Reason: Correct core localization. Supporting Evidence: file:human/COX6A1/COX6A1-deep-research-falcon.md Structural data place COX6A1 within human CIV purified from mitochondrial supercomplexes, supporting mitochondrial localization at the respiratory chain. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9865663 | ACCEPT | Summary: COX6A1 is a single-pass mitochondrial inner membrane subunit of Complex IV. Reason: Correct core localization. Supporting Evidence: file:human/COX6A1/COX6A1-deep-research-falcon.md COX6A1 is a **nuclear-encoded structural (stoichiometric) subunit** of mammalian COX/CIV that surrounds the catalytic core. |
| GO:0006091 generation of precursor metabolites and energy | TAS PMID:2549515 Sequence of a cDNA specifying subunit VIa of human cytochrom... | KEEP AS NON CORE | Summary: Generation of precursor metabolites and energy is a very broad metabolism term downstream of oxidative phosphorylation. Reason: Valid but too general to represent the core function of COX6A1. Supporting Evidence: file:human/COX6A1/COX6A1-deep-research-falcon.md COX6A1 functions within complex IV of the oxidative phosphorylation system, the terminal respiratory-chain complex that transfers electrons to oxygen and helps generate the proton gradient for ATP synthesis. |
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