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,regulate...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 potentialΔΨm 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 ATPinhibition and monomerization of CytOx.This is followed by increase ofΔΨm 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 highΔΨm,high ROS and low efficiency)and complex I(resting state with lowΔΨm,low ROS and high efficiency).展开更多
文摘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 potentialΔΨm 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 ATPinhibition and monomerization of CytOx.This is followed by increase ofΔΨm 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 highΔΨm,high ROS and low efficiency)and complex I(resting state with lowΔΨm,low ROS and high efficiency).
