COX6A1


Cytochrome c oxidase subunit 6A1, mitochondrial is a protein that in humans is encoded by the COX6A1 gene. Cytochrome c oxidase 6A1 is a subunit of the cytochrome c oxidase complex, also known as Complex IV, the last enzyme in the mitochondrial electron transport chain. A mutation of the COX6A1 gene is associated with a recessive axonal or mixed form of Charcot-Marie-Tooth disease.

Structure

The COX6A1 gene, located on the q arm of chromosome 12 in position 24.2, contains 3 exons and is 2,653 base pairs in length. The COX6A1 protein weighs 12 kDa and is composed of 109 amino acids. The protein is a subunit of Complex IV, a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. This nuclear gene encodes polypeptide 1 of subunit VIa, and polypeptide 1 is found in all non-muscle tissues. Polypeptide 2 of subunit VIa is encoded by a different gene, COX6A2, and is present only in striated muscles. These two polypeptides share 66% amino acid sequence identity.

Function

Cytochrome c oxidase 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 to drive ATP synthesis via protonmotive force. The mitochondrially-encoded subunits perform the electron transfer of 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.
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Clinical significance

A mutation leading to a 5 base pair deletion in the COX6A1 gene is associated with Charcot-Marie-Tooth disease. CMT is the most common inherited neuropathy and can result from mutations in over 30 different loci. Expression of COX6A1 is significantly reduced in affected individuals.
The Trans-activator of transcription protein of human immunodeficiency virus inhibits cytochrome c oxidase activity in permeabilized mitochondria isolated from both mouse and human liver, heart, and brain samples. Rapid loss of membrane potential occurs with submicromolar doses of Tat, and cytochrome c is released from the mitochondria.