title: Revisiting Kadenbach: Electron flux rate through cytochrome c-oxidase determines the ATP-inhibitory effect and subsequent production of ROS.
abstract: Mitochondrial respiration is the predominant source of ATP. Excessive rates of electron transport cause a higher production of harmful reactive oxygen species (ROS). There are two regulatory mechanisms known. The first, according to Mitchel, is dependent on the mitochondrial membrane potential that drives ATP synthase for ATP production, and the second, the Kadenbach mechanism, is focussed on the binding of ATP to Cytochrome c Oxidase (CytOx) at high ATP/ADP ratios, which results in an allosteric conformational change to CytOx, causing inhibition. In times of stress, ATP-dependent inhibition is switched off and the activity of CytOx is exclusively determined by the membrane potential, leading to an increase in ROS production. The second mechanism for respiratory control depends on the quantity of electron transfer to the Heme aa3 of CytOx. When ATP is bound to CytOx the enzyme is inhibited, and ROS formation is decreased, although the mitochondrial membrane potential is increased.
authors.affiliation: Cardiovascular Research Lab, Biochemical Pharmacological Research Center, Philipps-University Marburg, Marburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Vogt
authors.affiliation: Cardiovascular Research Lab, Biochemical Pharmacological Research Center, Philipps-University Marburg, Marburg, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Rhiel
authors.affiliation: Cardiovascular Research Lab, Biochemical Pharmacological Research Center, Philipps-University Marburg, Marburg, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Weber
authors.affiliation: Cardiovascular Research Lab, Biochemical Pharmacological Research Center, Philipps-University Marburg, Marburg, Germany.
authors.forename: Rabia
authors.initials: R
authors.lastname: Ramzan
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis / Q000378:metabolism*; D000494:Allosteric Regulation; D000818:Animals; D004579:Electron Transport; D003576:Electron Transport Complex IV / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D025261:Mitochondrial Proton-Translocating ATPases
keywords: allosteric inhibition; cytochrome c oxidase; enzyme kinetics; ischaemic preconditioning; phosphodiesterase inhibitors; reactive oxygen species