Review
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Biol Chem. Sep 27, 2020; 11(2): 52-61
Published online Sep 27, 2020. doi: 10.4331/wjbc.v11.i2.52
Regulation of cytochrome c oxidase contributes to health and optimal life
Bernhard Kadenbach
Bernhard Kadenbach, Department of Chemistry/Biochemistry, Fachbereich Chemie, Philipps-Universität Marburg, Marburg D-35043, Hessen, Germany
Author contributions: Kadenbach B solely contributed to this manuscript.
Conflict-of-interest statement: No conflict of interests.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Bernhard Kadenbach, DSc, PhD, Emeritus Professor, Department of Chemistry/Biochemistry, Fachbereich Chemie, Philipps-Universität Marburg, Marburg D-35043, Hessen, Germany. kadenbach@staff.uni-marburg.de
Received: April 16, 2020
Peer-review started: April 16, 2020
First decision: July 25, 2020
Revised: August 1, 2020
Accepted: August 24, 2020
Article in press: August 24, 2020
Published online: September 27, 2020
Abstract

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 ΔΨm and reactive oxygen species (ROS) formation at low healthy values. Stress signals increase cytosolic calcium leading to Ca2+-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 ΔΨm 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 ΔΨm, high ROS and low efficiency) and complex I (resting state with low ΔΨm, low ROS and high efficiency).

Keywords: Cytochrome c oxidase, Regulation of respiration, Allosteric ATP-inhibition, NDUFA4, Reversible phosphorylation, Efficiency of ATP synthesis, Dimerization of cytochrome c oxidase

Core Tip: This article describes the “allosteric ATP-inhibition of cytochrome c oxidase,” which prevents the formation of reactive oxygen species (ROS) under resting conditions in all eukaryotic cells by keeping the mitochondrial membrane potential ΔΨm at low values. Under stress – via increased calcium concentrations – this mechanism is switched off, accompanied by increased rates of ATP-synthesis with decreased efficiency and formation of deleterious ROS. A hypothesis is described in which NDUFA4 changes its position from complex I to cytochrome c oxidase when the metabolic state changes from the rest to excited state under stress.