Mitochondrial energy metabolism is regulated via nuclear-coded subunits of cytochrome c oxidase.
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 delta p. cAMP-dependent phosphorylation of COX switches on and Ca2+-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 delta p (mainly delta psi(m)) low. Hormone induced Ca2+-dependent dephosphorylation results in loss of ATP-inhibition, increase of respiration and delta p with consequent slip in proton pumping. Slip in COX increases the free energy of reaction, resulting in increased rates of respiration, thermogenesis and ATP-synthesis. Increased delta psi(m) stimulates production of reactive oxygen species (ROS), mutations of mitochondrial DNA and accelerates aging. Slip of proton pumping without dephosphorylation and increase of delta p 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 delta p, ROS production and slip but without dephosphorylation of COX.
Kadenbach
B
B
Fachbereich Chemie, Philipps-Universität, Marburg, Germany. Kadenbach@chemie.uni-marburg.de
Hüttemann
M
M
Arnold
S
S
Lee
I
I
Bender
E
E
D000818:Animals; D002467:Cell Nucleus / Q000235:genetics*; D019069:Cell Respiration; D016922:Cellular Senescence; D003576:Electron Transport Complex IV / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D004734:Energy Metabolism; D006801:Humans; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D011487:Protein Conformation; D021122:Protein Subunits
D021122:Protein Subunits; D003576:Electron Transport Complex IV