Elsevier

Mitochondrion

Volume 13, Issue 1, January 2013, Pages 1-6
Mitochondrion

Review
High efficiency versus maximal performance — The cause of oxidative stress in eukaryotes: A hypothesis

https://doi.org/10.1016/j.mito.2012.11.005Get rights and content

Abstract

Degenerative diseases are in part based on elevated production of ROS (reactive oxygen species) in mitochondria, mainly during stress and excessive work under stress (strenuous exercise). The production of ROS increases with increasing mitochondrial membrane potentialΨm). A mechanism is described which is suggested to keep ΔΨm at low values under normal conditions thus preventing ROS formation, but is switched off under stress and excessive work to maximize the rate of ATP synthesis, accompanied by decreased efficiency. Low ΔΨm and low ROS production are suggested to occur by inhibition of respiration at high [ATP]/[ADP] ratios. The nucleotides interact with phosphorylated cytochrome c oxidase (COX), representing the step with the highest flux-control coefficient of mitochondrial respiration. At stress and excessive work neural signals are suggested to dephosphorylate the enzyme and abolish the control of COX activity (respiration) by the [ATP]/[ADP] ratio with consequent increase of ΔΨm and ROS production. The control of COX by the [ATP]/[ADP] ratio, in addition, is proposed to increase the efficiency of ATP production via a third proton pumping pathway, identified in eukaryotic but not in prokaryotic COX. We conclude that ‘oxidative stress’ occurs when the control of COX activity by the [ATP]/[ADP] ratio is switched off via neural signals.

Highlights

► A mechanism is described which prevents high ΔΨm and ROS formation in cells ► High ROS in living cells (oxidative stress) leads to aging and degenerative diseases ► The mechanism is switched on by phosphorylation of cytochrome c oxidase (COX) ► It is switched off under stress or excessive work by dephosphorylation of COX ► High efficiency of ATP synthesis occurs at low ΔΨm by increased H+/e − ratio in COX

Introduction

It is generally accepted that oxidative damage represents a contributing factor in the loss of physiological functions during aging (Huang and Manton, 2004, Sohal and Orr, 2012), and in the development of multiple degenerative diseases (Trachootham et al., 2008, Valko et al., 2007). ROS (reactive oxygen species) are produced in cells by different pathways and low concentrations have signaling functions as second messengers (Bae et al., 2011, Barbieri and Sestili, in press, Finkel, 2011, Kvietys and Granger, 2012). High amounts of ROS are produced in mitochondria during stress, e.g. after ischemia/reperfusion (Solaini et al., 2010, Zhang et al., 2011) or after excessive work (strenuous exercise) under stress (Balakrishnan and Anuradha, 1998, Jackson et al., 1985, Packer, 1997). The production of ROS in mitochondria is mainly based on high membrane potentials (ΔΨm) (Korshunov et al., 1997, Liu, 1997, Murphy, 2009, Rottenberg et al., 2009), or high NADH/NAD+ ratios (Adam-Vize and Chinopoulos, 2006). The molecular basis maintaining low ΔΨm in vivo, however, is not fully understood. Here we describe a physiological mechanism which is suggested to prevent high ΔΨm and mitochondrial ROS production in cells/tissues under normal conditions, accompanied by high efficiency of ATP production. The mechanism is proposed to be switched off under stress or at excessive work associated with stress in order to maximize the rate of ATP synthesis (energetic output), however, at the expense of decreased efficiency and increased ΔΨm and ROS production (oxidative stress), finally accelerating aging and the formation of degenerative diseases. The hypothesis does not exclude the healthy effect of excessive work (strenuous exercise), if performed without stress (Fig. 1).

Section snippets

ATP synthesis in mitochondria through the generation of ΔΨm

All manifestations of life require energy which is almost exclusively supplied by ATP. In animals, more than 95% of ATP is synthesized in mitochondria by oxidative phosphorylation (OxPhos). As originally described by Mitchell (1966), the released energy is transiently stored in a proton gradient across the inner mitochondrial membrane, established by three proton pumps, the complexes I (NADH:ubiquinone oxidoreductase), III (cytochrome bc1 complex), and IV (cytochrome c oxidase). The proton

Second mechanism of respiratory control (RC2)

A “second mechanism of respiratory control” (RC2) (Kadenbach and Arnold, 1999) was discovered in 1997, based on the allosteric inhibition of cytochrome c oxidase (COX) activity at high [ATP]/[ADP] ratios via exchange of bound ADP by ATP at the matrix domain of subunit IV (Arnold and Kadenbach, 1997). The RC2 is independent of ΔΨm and half-maximal inhibition of respiration occurs at [ATP]/[ADP] = 28 (Arnold and Kadenbach, 1999). In rat heart, based on 31P-NMR data, cytosolic [ATP]/[ADP] ratios of

Formation of reactive oxygen species (ROS) in mitochondria

High and deleterious amounts of ROS (mainly the superoxide radical anion O2. −) are produced in mitochondria under stress conditions, e.g. after ischemia/reperfusion (Solaini et al., 2010, Zhang et al., 2011), or at excessive work (Balakrishnan and Anuradha, 1998, Jackson et al., 1985, Packer, 1997). The sites of ROS production are mainly complexes I (Kussmaul and Hirst, 2006, Lambert and Brand, 2004) and III (Dröse and Brandt, 2008). The superoxide is produced by one electron transfer to

Preventing oxidative stress (ROS formation) in living cells

In vivo, a decrease of ΔΨm and ROS formation occurs or a further increase is prevented by different mechanisms. First through intrinsic uncoupling of OxPhos including a decrease of H+/e stoichiometry in complex IV, either at high ΔΨm (Kadenbach, 2003) or, only in the muscle-type isoform of COX, at very high [ATP]/[ADP] ratios (Frank and Kadenbach, 1996, Lee and Kadenbach, 2001).

Second by extrinsic uncoupling of OxPhos based on the proton leak of the inner mitochondrial membrane (Jastroch et

Switching on and off the RC2 by reversible phosphorylation of COX

In purified COX from bovine heart, either dissolved in Tween-20 or reconstituted in liposomes, the allosteric ATP-inhibition of COX (RC2) could be switched on by phosphorylation with protein kinase A (PKA), cAMP and ATP, and switched off by subsequent dephosphorylation with protein phosphatase 1 (PP1) (Lee et al., 2001, Lee et al., 2002). It was postulated that Ser-441, located at the intermembrane side of bovine heart COX subunit I, represents the phosphorylation site switching on and off the

Proton pumping of COX is variable

Under resting conditions the RC2 is suggested to maintain high efficiency of OxPhos by lowering ΔΨm, accompanied by lower rates of ATP synthesis and ROS production. During excessive work (or under stress) this mechanism is suggested to be switched off allowing maximal rates of ATP synthesis at lower efficiency (Stucki, 1980). We postulate that high efficiency is partly achieved by increased H+/e stoichiometry of COX. Although it is generally believed that the H+/e stoichiometry of COX is 1.0

Concluding remarks

The proposed mechanism suggests in animals a switch of OxPhos between high efficiency at low ΔΨm and low ROS formation (RC2 on), and activated state with maximal rates of ATP synthesis (maximal energetic output) at lower efficiency accompanied by elevated ΔΨm and ROS formation (RC2 off). This allows the organisms to adapt to variable ATP demands e.g. during sleep or normal work (high efficiency) and at stress or excessive work (high rates of ATP synthesis). The RC2 is suggested to be switched

Acknowledgements

We gratefully acknowledge the critical reading of the manuscript by Shinya Yoshikawa and Bernd Ludwig. The work was supported by the Deutsche Forschungsgemeinschaft (grant number: DFG Ka 192/40-1).

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