Mitochondrial free radical generation, oxidative stress, and aging1
Introduction
Over 95% of all the oxygen we breathe undergoes a concerted tetravalent reduction to produce water in a reaction catalyzed by cytochrome oxidase (cytochrome c, oxygen, oxidoreductase) of complex IV in the mitochondrial electron transport chain (O2 + 4e− + 4H+ → 2H2O). Cytochrome oxidase is the terminal electron acceptor in the chain and must give up its reducing equivalents to allow continued electron transport: if electrons stop flowing through the chain, the protonmotive force dissipates and ATP production cannot continue. Thus, the major role of oxygen for all aerobic organisms is simply to act as a sink or dumping ground for electrons.
Although the mitochondrial electron transport chain is a very efficient system, the very nature of the alternating one-electron oxidation-reduction reactions it catalyzes (generating a constantly alternating series of “caged” radicals) predispose each electron carrier to side reactions with molecular oxygen. Thus, for example, as ubiquinone within the electron transport chain cycles between the quinone (fully oxidized) to semiquinone (one-electron reduction product) to quinol (fully reduced by two electrons) states, there is a tendency for an electron to pass to oxygen directly (generating O2•−) instead of to the next electron carrier in the chain. Several iron-sulfur clusters within the respiratory chain are also subject to such toxic, O2•−-generating, side reactions with oxygen. Thus it is commonly held that mitochondrial generation of O2•− represents the major intracellular source of oxygen radicals under physiological conditions. With estimates of 1–2% of the total daily oxygen consumption going to mitochondrial O2•− generation, a 60 kg woman would produce some 160–320 mmol of superoxide each day from mitochondrial respiration alone (based on an O2 consumption of 6.4 l/kg/day) and an 80 kg man would produce some 215–430 mmol of O2•−per day.
In addition to these toxic electron transport chain reactions of the inner mitochondrial membrane, the mitochondrial outer membrane enzyme monoamine oxidase catalyzes the oxidative deamination of biogenic amines and is a quantitatively large source of H2O2 that contributes to an increase in the steady state concentrations of reactive species within both the mitochondrial matrix and cytosol. In this article we review the mitochondrial rates of production and steady state levels of these reactive oxygen species.
Reactive oxygen species cause damage to mitochondrial components and initiate degradative processes. Such toxic reactions form the central dogma of “The Free Radical Theory of Aging.” In this article we review mitochondrial DNA, RNA, and protein modifications by oxidative stress and the enzymatic removal of such oxidatively damaged products by nucleases and proteases. The possible contributions of these processes to apoptosis and aging are also discussed.
Section snippets
The mitochondrial generation of oxidants
The superoxide anion radical (or superoxide, or O2•−) and hydrogen peroxide (H2O2), respectively, the products of the univalent and bivalent reduction of oxygen (O2), are produced during normal aerobic metabolism and constitute physiological intracellular metabolites. Several reactions in biological systems contribute to the steady state concentrations of O2•− and H2O2, although mitochondria seem to be quantitatively the most important cellular source. The electron-transfer chain of
Oxidative stress and mitochondrial damage
Mitochondria seem to be (quantitatively) the most important subcellular site of O2•− and H2O2 production in mammalian organs, and the steady state concentration of O2•− in the mitochondrial matrix is about 5- to 10-fold higher than that in the cytosolic and nuclear spaces. Hence, mitochondrial components are exposed to a relatively high flux of and H2O2. Also, H2O2 generated during the outer membrane monoamine oxidase-catalyzed oxidation of amines seems to be a central metabolite contributing
Summary and conclusions
The Electron transfer system of the mitochondrial inner membrane is clearly a major source of superoxide production; resulting in dismutation to form hydrogen peroxide (H2O2), which can further react to form the hydroxyl radical (HO). In addition to these toxic electron transport chain reactions of the inner mitochondrial membrane, the mitochondrial outer membrane enzyme monoamine oxidase catalyzes the oxidative deamination of biogenic amines and is a quantitatively large source of H2O2. This
Acknowledgements
This research was supported by grants from the National Institutes of Health AG16718 (E.C.) and by Grant ES-03598 (K.J.A.D.) from the National Institute of Environmental Health Sciences and Grant AG-16256 (K.J.A.D.) from the National Institute on Aging, NIH.
References (62)
- et al.
Superoxide radical and hydrogen peroxide in mitochondria
- et al.
The metabolism of tyramine by monoamine oxidase A/B causes oxidative damage to mitochondrial DNA
Arch. Biochem. Biophys.
(1996) - et al.
Nitric oxide inhibits electron transfer and increases superoxide radical production in rat heart mitochondria and submitochondrial particles
Arch. Biochem. Biophys.
(1996) - et al.
The regulation of mitochondrial oxygen uptake by redox reactions involving nitric oxide and ubiquinol
J. Biol. Chem.
(1999) - et al.
Regulation of mitochondrial respiration by ADP, oxygen, and nitric oxide
Methods Enzymol
(1999) - et al.
The reaction of ubiquinols with nitric oxide
- et al.
Mitochondrial production of superoxide anions and its relationship to the antimycin-insensitive respiration
FEBS Lett
(1975) - et al.
Assay of metabolic superoxide production in Escherichia coli
J. Biol. Chem.
(1991) - et al.
Inactivation-reactivation of aconitase in Escherichia colia sensitive measure of superoxide
J. Biol. Chem.
(1992) - et al.
Peroxide removal by selenium-dependent and selenium-independent glutathione peroxidases in hemoglobin-free perfused rat liver
J. Biol. Chem.
(1978)
Rat liver glutathione peroxidasepurification and study of multiple forms
Arch. Biochem. Biophys.
Detection of catalase in rat heart mitochondria
J. Biol. Chem.
Hydroxyl radical generation during mitochondrial electron transfer and the formation of 8-hydroxy-desoxyguanosine in mitochondrial DNA
Arch. Biochem. Biophys.
Oxidants in mitochondriafrom physiology to diseases
Biochim. Biophys. Acta
Mitochondrial decay in aging
Biochim. Biophys. Acta
The role of mitochondrial glutathione in DNA base oxidation
Biochim. Biophys. Acta
Singlet oxygen induced single-strand breaks in plasmid pBR322 DNAthe enhancing effect of thiols
Biochim. Biophys. Acta
Copper-catalyzed DNA damage by ascorbate and hydrogen peroxidekinetics and yield
Free Radic. Biol. Med.
Down-regulation of mammalian mitochondrial RNA’s during oxidative stress
Free Radic. Biol. Med.
16S mitochondrial ribosomal RNA degradation is associated with apoptosis
Free Radic. Biol. Med.
Oxidative stress causes a general, calcium dependent degradation of mitochondrial polynucleotides
Free Radic. Biol. Med.
Polynucleotide degradation during early stage response to oxidative stress is specific to mitochondria
Free Radic. Biol. Med.
The oxidative inactivation of mitochondrial electron transport chain components and ATPase
J. Biol. Chem.
Peroxynitrite increases the degradation of aconitase and other cellular proteins by proteasome
J. Biol. Chem.
Degradation of oxidatively denatured proteins in Escherichia coli
Free Radic. Biol. Med.
Oxidatively denatured proteins are degraded by an ATP-independent pathway in Escherichia coli
Free Radic. Biol. Med.
Mitochondrial NADH dehydrogenase-catalyzed oxygen radical production by adriamycin, and the relative inactivity of 5-iminodaunorubicin
FEBS Lett
Comparative cardiac oxygen radical metabolism by anthracycline antibiotics, mitoxantrone, bisantrene, 4′-(9-acridinylamino)-methanesulfon-m-anisidide, and neocarzinostatin
Biochem. Pharmacol.
Redox cycling of anthracyclines by cardiac mitochondriaI. Anthracycline radical formation by NADH dehydrogenase
J. Biol. Chem.
A. Redox cycling of anthracyclines by cardiac mitochondria: II. Formation of superoxide anion, hydrogen peroxide, and hydroxyl radical
J. Biol. Chem.
Free radicals and tissue damage produced by exercise
Biochem. Biophys. Res. Commun.
Cited by (2521)
Current biomarkers and treatment strategies in Alzheimer disease: An overview and future perspectives
2024, IBRO Neuroscience ReportsEffect of wet-aging on meat quality and exudate metabolome changes in different beef muscles
2024, Food Research InternationalClinical markers of HIV predict redox-regulated neural and behavioral function in the sensorimotor system
2024, Free Radical Biology and MedicineAntifungal activity and mechanism of Litsea cubeba (Lour.) Persoon essential oil against the waxberry spoilage fungi Penicillium oxalicum and its potential application
2024, International Journal of Food Microbiology
- 1
This article is dedicated to the memory of our dear friend, colleague, and mentor Lars Ernster (1920–1998), in gratitude for all he gave to us.