Trends in Biochemical Sciences
ReviewMitochondria, oxygen free radicals, disease and ageing
Section snippets
Physiological ROS production
The production of superoxide by the respiratory chain is estimated to be at rates somewhat less than 1% of the total rate of electron transport from NADH to oxygen7, 8, 9. The physiological fate of the hydrogen peroxide generated on either side of the mitochondrial membrane by MnSOD or CuZnSOD is to be processed by glutathione peroxidase (GPX) to water in a reaction that converts reduced glutathione (GSH) to oxidized glutathione (GSSG)1, 8:
The GPX located in the mitochondria
Complex I and superoxide production
Oxidative phosphorylation in mitochondria is carried out by four electron-transporting complexes (I–IV) and one H+-translocating ATP synthetic complex (complex V) (Fig. 1). Two of these complexes were shown to be responsible for much of the superoxide generated by mitochondria: complex I, the NADH-ubiquinone oxidoreductase, and complex III, the ubiquinol-cytochrome c oxidoreductase7, 8, 11. Mammalian complex I is a large macromolecular assembly of proteins comprising 34 subunits encoded by the
Complex III and superoxide production
Complex III (ubiquinol-cytochrome c oxidoreductase) is responsible for taking reducing equivalents, which are generated in complexes I and II and contained in ubiquinol, and transfer-ring them through reactions with cytochrome b, the Rieske iron-sulphur protein and cytochrome c1 to the final electron acceptor cytochrome c. There are also two species of semiquinone generated in the mechanistic operation of complex III (Ref. 21). The Q-cycle mechanism proposed for the operation of the ubiquinol
Damage caused by mitochondrially generated ROS
Under normal circumstances, the rate of generation of superoxide from mitochondria is rather low and does little damage, simply because it is efficiently removed by the superoxide dismutases. However, circumstances can arise for a variety of reasons (e.g. ingested chemicals that act as radical amplifiers, medically applied high concentrations of oxygen, or during periods of reperfusion of tissues with oxygen following ischaemia) where high rates of superoxide production do occur. Superoxide
Oxygen free radical production in human complex I deficiency
A survey of patients with inherited disorders of the mitochondrial respiratory chain showed that fibroblast cell lines from patients with complex I deficiency displayed significant elevations of MnSOD, sometimes two- to threefold, whereas patients with defects in complex III, IV or V did not19, 20, 27, 28. Complex I deficiency has a wide spectrum of phenotypes varying from exercise intolerance (EI) to cataracts and developmental delay (CD), Leigh disease (LD) with degeneration of the basal
Evidence for ROS-induced mitochondrial damage associated with ageing
There is a wealth of circumstantial evidence linking the production of oxygen free radicals with the process of ageing. Graphs showing an inverse relationship in a variety of different animal species between life span and (i) expression of CuZnSOD (31, 32), (ii) basal metabolic rate33, (iii) mitochondrial production34 and (iv) mitochondrial hydrogen superoxide production35, are compelling in that they suggest that animals with more rapid rates of basal metabolism have faster rates of ROS
Overexpression of superoxide dismutases
Because the damage inherent from oxygen free radical production by the mitochondrial respiratory chain can be ameliorated by the judicious application of anti-oxidants and anti-oxidant enzymes, it has been postulated that more of these enzymes would, by necessity, reduce damage and therefore might actually prolong lifespan41. Although this was shown to be true for overexpression of CuZnSOD in fruitflies28, 41, experiments on transgenic mice have been disappointing in this regard. The presence
Reactive oxygen species – direct mediators of ageing or agents responsible for modulation of a more fundamental ageing process
That oxygen free radicals can contribute in some way to the ageing process is suggested by a number of experimental observations, as discussed above. However, the maximum variance in mammalian systems that can be elicited from manipulation of oxygen free radical production is an extension of life span of ∼40%36, 48, 49. Clearly, the role of ROS in ageing needs to be put into context with respect to other mechanisms that are known to be connected with life span, particularly the phenomenon of
Acknowledgements
B.H.R. and S.R. are supported by The Heart and Stroke Association of Canada and the Medical Research Council of Canada.
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