Regulation of cytochrome c oxidase contributes to health and optimal life

The generation of cellular energy in the form of ATP occurs mainly in mitochondria by oxidative phosphorylation. Cytochrome c oxidase (CytOx), the oxygen accepting and rate-limiting step of the respiratory chain, regulates the supply of variable ATP demands in cells by “allosteric ATP-inhibition of CytOx.” This mechanism is based on inhibition of oxygen uptake of CytOx at high ATP/ADP ratios and low ferrocytochrome c concentrations in the mitochondrial matrix via cooperative interaction of the two substrate binding sites in dimeric CytOx. The mechanism keeps mitochondrial membrane potential ΔΨ(m) and reactive oxygen species (ROS) formation at low healthy values. Stress signals increase cytosolic calcium leading to Ca(2+)-dependent dephosphorylation of CytOx subunit I at the cytosolic side accompanied by switching off the allosteric ATP-inhibition and monomerization of CytOx. This is followed by increase of ΔΨ(m) and formation of ROS. A hypothesis is presented suggesting a dynamic change of binding of NDUFA4, originally identified as a subunit of complex I, between monomeric CytOx (active state with high ΔΨ(m), high ROS and low efficiency) and complex I (resting state with low ΔΨ(m), low ROS and high efficiency).