Mitochondrial energy metabolism is regulated via nuclear-coded subunits of cytochrome c oxidase

Abstract

A new mechanism on regulation of mitochondrial energy metabolism is proposed on the basis of reversible control of respiration by the intramitochondrial ATP/ADP ratio and slip of proton pumping (decreased H +/e − stoichiometry) in cytochrome c oxidase (COX) at high proton motive force Δp. cAMP-dependent phosphorylation of COX switches on and Ca 2+-dependent dephosphorylation switches off the allosteric ATP-inhibition of COX (nucleotides bind to subunit IV). Control of respiration via phosphorylated COX by the ATP/ADP ratio keeps Δp (mainly ΔΨ m) low. Hormone induced Ca 2+-dependent dephosphorylation results in loss of ATP-inhibition, increase of respiration and Δp with consequent slip in proton pumping. Slip in COX increases −ΔG o′, resulting in increased rates of respiration, thermogenesis and ATP-synthesis. Increased ΔΨ m stimulates production of reactive oxygen species (ROS), mutations of mitochondrial DNA and accelerates aging. Slip of proton pumping without dephosphorylation and increase of Δp is found permanently in the liver-type isozyme of COX (subunit VIaL) and at high intramitochondrial ATP/ADP ratios in the heart-type isozyme (subunit VIaH). High substrate pressure (sigmoidal v/s kinetics), palmitate and 3,5-diiodothyronine (binding to subunit Va) increase also Δp, ROS production and slip but without dephosphorylation of COX.