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COX6A1 is a nuclear-encoded accessory/structural subunit of mitochondrial Complex IV (cytochrome c oxidase), not a catalytic subunit; reviews place it among nuclear subunits that modulate COX activity and/or stability/assembly.
"COX6A1 is a **nuclear-encoded structural (stoichiometric) subunit** of mammalian COX/CIV that surrounds the catalytic core. Reviews emphasize that these nuclear-encoded subunits (including COX6A) are generally **not the catalytic center** but **modulate COX activity and/or stability/assembly**."
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Cryo-EM of intact human Complex IV identifies COX6A1 as one of the 14 subunits and shows that human COX6A1 replaces bovine COX6A2 in the resolved enzyme.
"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**"
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The COX6A family has two tissue-specific isoforms; COX6A1 (liver type) is ubiquitously expressed and COX6A2 (heart type) is restricted to heart and skeletal muscle.
"An authoritative review summarizes that the COX6A family has **two tissue-specific isoforms**"
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COX6A is proposed to stabilize quaternary structure by contacting COX1 of the opposite monomer in dimeric models and to influence proton pumping efficiency and allosteric regulation of cytochrome c oxidase.
"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."
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COX6A is a late-incorporating nuclear-encoded subunit in modular CIV assembly, consistent with dynamic CIV composition.
"COX6A is discussed as a **late-incorporating nuclear-encoded subunit** in modular/sequential assembly models, supporting a concept that CIV composition can be dynamic (including potential isoform exchange/quality control)."
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COX6A1 functions within Complex IV of the oxidative phosphorylation system, the terminal respiratory-chain complex transferring electrons to oxygen and generating the proton gradient for ATP synthesis.
"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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COX6A1 is localized to the mitochondrial inner membrane in the context of cytochrome c oxidase/respirasome assemblies.
"COX6A1 is a mitochondrial complex IV subunit embedded in the inner mitochondrial membrane context of cytochrome c oxidase/respirasome assemblies."
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Experimentally, selective loss of COX6A1 (via PLK1-dependent autophagy in gefitinib hepatotoxicity) decreases Complex IV activity and increases apoptosis; COX6A1 overexpression rescues these phenotypes.
"COX6A1 reduction is linked to **decreased complex IV activity** and increased apoptosis, while **COX6A1 overexpression rescues apoptosis and RCC IV dysfunction**."