Sci. Aging Knowl. Environ., 16 October 2002
Vol. 2002, Issue 41, p. pe16
[DOI: 10.1126/sageke.2002.41.pe16]


Mitochondrial Abnormalities and Oxidative Imbalance in Neurodegenerative Disease

Osamu Ogawa, Xiongwei Zhu, George Perry, and Mark A. Smith

The authors are at the Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. E-mail: mas21{at};2002/41/pe16

Key Words: coenzyme Q10 • antioxidant • mitochondria • oxidative stress • Parkinson's disease • Alzheimer disease


Parkinson's disease (PD), the most common disease involving motor system degeneration and the second most common neurodegenerative disease after Alzheimer disease (AD), is characterized by severely afflicted dopaminergic neurons within the substantia nigra (SN) region of the brain and the presence of Lewy bodies in neurons (see Constantino Case Study) (1). Normally, dopamine produced in the SN is moved to the caudate nucleus and the putamen, where it is involved in stimulating and coordinating the body's motor movements. However, in PD, the neurons that produce dopamine in the SN die, reducing the overall supply of dopamine and compromising the brain's capacity to effectuate movement. The SN is more vulnerable to oxidative damage than the brain as a whole because of its unique biochemical features; these include a high content of oxidizable dopamine (2), neuromelanin (3, 4), polyunsaturated fatty acids, and iron (3, 5, 6), as well as a relatively low antioxidant complement coupled with a high metabolic rate. Furthermore, aging makes the antioxidant defenses less competent. Oxidative phosphorylation abnormalities found in PD impair energetics in the SN mitochondria (7-11), also intensifying oxygen free-radical generation. Although the causes of PD are not fully understood, this intrinsic susceptibility, together with the cumulative contributions of exogenous (environmental) oxidant stressors, suggests that PD is primarily a multifactorial, oxidative disease.

In the October 2002 issue of Archives Neurology , Shults et al. (12) report the results of a clinical trial where patients with PD were treated with coenzyme Q10 (CoQ10), an antioxidant and cofactor for several mitochondrial enzymes. In this Perspective, we discuss the results of Shults et al. and the implications of their findings in the context of oxygen metabolism.

Oxygen Metabolism and Parkinson's Disease

All of the body's cells produce life energy and simultaneously generate oxygen free radicals (oxyradicals). The resultant oxidative burden is an obligatory, unavoidable by-product of oxygen-based (aerobic) respiration, and these oxyradicals are so highly reactive that they have the potential to destroy the living system (see "The Two Faces of Oxygen") (13). The major cellular "hot spots," where the bulk of oxyradicals are produced and antioxidant defenses are normally most challenged, are the semi-independent organelles called mitochondria (see Nicholls Perspective). Present in all human cells, mitochondria are the cell's energy powerhouses in that they generate the vast majority of the adenosine 5�-triphosphate (ATP) that drives life processes (14). Mitochondria have their own DNA and manage the oxidative phosphorylation process. Because mitochondria use 90% or more of the cell's available oxygen to make ATP, they also generate 90% or more of the oxyradicals that make up the endogenous oxidative burden (15). The oxidative phosphorylation complexes are aggregates of enzymes that are functionally linked and distributed in groups throughout the inner membranes of the mitochondria. Complexes I, II, III, IV, and V occur in spatial sequences that optimize electron transfer efficiency while minimizing single-electron "leakage" to oxygen, which would generate oxyradicals (16). These mitochondrial electron transfer complexes use highly electrophilic molecular oxygen to create an electronic potential gradient, which pulls electrons through this series of five cytochrome-protein complexes. The complexes sequentially extract the electron's energy, converting it to ATP. However, during the transfers, single electrons escape enzymatic control. These combine with oxygen to create oxygen free radicals, using ~2% of all oxygen consumed. To protect against destruction by this flux of oxyradicals, the mitochondria have sophisticated antioxidant defenses, but inevitably, a few oxyradicals slip through to attack biomolecules. One of the most striking features of the human brain is its respiratory requirements: 20 to 25% of total-body basal respiration occurs in the less than 2% of the body's mass occupied by the brain, and most of that is in the even smaller mass occupied by neurons. The total dependence of the brain on oxygen is shown by the failure of neurons to survive under ischemic conditions.

Patients with PD have abnormalities in oxidative phosphorylation (17) that impair their mitochondrial energy generation and almost certainly increase their endogenous oxidative burden (7-11). The observation that the notorious parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a by-product of heroin synthesis, can cause parkinsonism through the inhibition of complex I stimulated studies of mitochondrial function in PD (see Andersen et al. Review). It is now clear that PD patients have mitochondrial energetic impairment that closely resembles that attributable to MPTP but is apparently constitutive in origin (8-11). Schapira and co-workers (7) were the first to report that mitochondrial complex I activity was selectively reduced in the SN of patients with PD, and this was subsequently confirmed by others (8-11). Haas et al. (17) found that this abnormality was not confined to the brain: Using platelets purified from early-stage patients not on medication for PD, they documented abnormalities of complex I and possibly also complexes II and III in their mitochondria.

The Function of CoQ10 in the Mitochondria

CoQ10 or ubiquinone is a fat-soluble vitamin-like substance present in every cell of the body. It serves as a potent antioxidant and as a coenzyme for three mitochondrial enzymes (complexes I, II, and III) (15). CoQ10 is synthesized in all tissues, and appropriate concentrations of this coenzyme are maintained both by CoQ10 intake and by the body's synthesis of CoQ10. However, aging, genetic mutations, and statin-type drugs can cause a decrease of CoQ10 in serum or tissues (18), and this decline in CoQ10 concentrations might relate to the occurrence of diverse diseases, such as periodontal disease (19), breast cancer (20), and human immunodeficiency virus infection (21). In fact, there have been numerous reports of the benefits of CoQ10 in patients with heart disease, although the studies were often not controlled (22). To date, the best work documents a significant reduction in the cardiac toxicity of the chemotherapy drug, Adriamycin, in patients also taking CoQ10 (23-25).

The cardiac toxicity of Adriamycin and related drugs may well relate to free-radical generation, and this might explain the benefit of CoQ10 in its capacity as a free-radical scavenger. The antioxidant or free-radical quenching properties of CoQ10 serve to greatly reduce oxidative damage to tissues, as well as significantly inhibit the oxidation of low density lipoprotein (LDL) cholesterol (CoQ10 is much more efficient in protecting LDL from oxidation than is vitamin E) (26, 27). This has important implications for the treatment of ischemia and reperfusion injury, as well as having the potential for slowing the development of atherosclerosis.

CoQ10 and Parkinon's Disease

In PD, given the confirmed presence of mitochondrial energetic abnormalities in the SN and elsewhere in the afflicted brain, nutrients that safely boost mitochondrial function deserve further exploration for clinical benefit. Two separate groups reported that CoQ10 is significantly reduced in mitochondria isolated from the brain (28) and platelets (29) of PD patients. Decreased complex I activity was strongly correlated with reduced mitochondrial content of CoQ10. Shults and collaborators (30) gave three different oral doses of CoQ10 with vitamin E daily to 15 PD patients and, after 1 month, found that complex I activity was increased. At 600 mg/day of CoQ10, complex I activity doubled to well within the range seen in healthy subjects, but small sample sizes precluded attainment of statistical significance.

Now, in the October 2002 issue of Archives of Neurology, Shults et al. (12) report that oral supplementation with CoQ10 at a safe and well-tolerated dosage (1200 mg/day) for 16 months reduced the worsening of PD, as reflected in the total Unified Parkinson Disease Rating Score (UPDRS). The greatest effects were seen in the patients' ability to carry out activities of daily living (part II of the UPDRS; part I assesses mental activity, behavior, and mood, while part III assesses motor function). They also showed that platelets from patients taking CoQ10 displayed increased activity in complexes I and III of the electron transport chain, which rely for function on endogenous CoQ10 in the mitochondria. These data imply that CoQ10 exerts its beneficial effects by modulating mitochondrial function. Their data are consistent with the hypothesis that mitochondrial dysfunction plays a role in the pathogenesis of PD and that treatments targeted at mitochondria might ameliorate the functional decline in PD. Their data also suggest that in the treatment of neurological disorders that show evidence of dysfunction in complex I or complex II, such as PD and Huntington's disease, CoQ10 dosages might need to be much higher than those previously tried.

Mitochondrial Abnormalities and Neurodegenerative Disease

Increasing evidence now suggests the involvement of mitochondrial abnormalities in the etiology of neurodegenerative diseases other than PD. For example, a number of studies have found a deficiency in the activity of complex IV (cytochrome c oxidase) of the mitochondrial electron transport chain in the cerebral cortex and platelets of patients with AD, relative to normal controls (31). In addition, it was shown recently that mitochondrial abnormalities clearly are a source of reactive oxygen species (ROS), which cause oxidative damage of the neuronal perinuclear region (32-35).

When 8-hydroxyguanosine (8-OHG) is used as a marker of nucleic acid oxidation, oxidative damage in AD can be seen to occur throughout the neuronal cell body, and immunoelectron microscopy shows that the damage is predominantly in the cytosol. This distribution of damage is mostly concentrated at ribonuclease-sensitive sites, which indicates that the damage is in RNA, rather than DNA, molecules. Also, 8-OHG is the product of ·OH attack on guanosine bases in nucleic acids and has a radius of diffusion of only nanometers. This implies that the source of reactive oxygen activity must be in close physical proximity to the damage (that is, within the neuronal cytoplasm) and, therefore, must be generated in the cytosol in close proximity to RNA. The cytosolic site of damage seemingly excludes mitochondria, which contain little 8-OHG. On the basis of this observation, we hypothesize that mitochondria are key players in a complex relationship between O2- and H2O2 generated by the mitochondria and redox-active metals in the cytosol, which themselves result from mitochondrial abnormalities (36). O2- and H2O2 react with these cytosolic metals to produce ·OH, which in turn causes damage in the cell. This mechanism places mitochondrial abnormalities at the center of AD pathogenesis.

In understanding how mitochondria might be involved in neurodegeneration, we must consider that they produce O2- as part of their normal function and in greater quantities when respiration is compromised. While O2- diffuses poorly past membranes, its dismutation product, H2O2, can do so freely. H2O2 can be converted into ·OH in the presence of redox metals, such as iron or copper. It is noteworthy that both redox-active iron (37) and copper (38) are prominent in the lesions of AD (senile plaques and neurofibrillary tangles; see Honig Case Study), as well as within cytoplasmic granules and in the cytosol of all vulnerable neurons. This distribution closely parallels the distribution of 8-OHG. Taken together with the observed mitochondrial alterations, these findings suggest that the source of ROS responsible for neuronal oxidative damage is consequent to the complex interplay between abnormalities of mitochondria and metal homeostasis (1).

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Fig. 1. The interplay between mitochondrial by-products and metal homeostasis. The black oval represents the mitochondria, with its inner membranes (black lines) and proteins of the electron transport chain (red circles). H2O2 is produced in the mitochondria, diffuses to the cytosol, and is converted to ROS by redox-active metals.

For example, in AD, researchers have observed increased expression of the cytosolic enzyme heme oxygenase-1 (39), an oxidative stress-inducible protein that catalyzes the production of free, redox-active iron. Sequestering of this iron in a "redox-inactive" form might serve to reduce redox activity in the brain (38). Furthermore, morphometric analysis demonstrates a significant decrease in the number of mitochondria in vulnerable neurons in AD (35). These observations, coupled with the detection of increased oxidative damage (as measured with 8-OHG), indicate that vulnerable neurons in AD have an increase in mitochondrial degradation products, which might result from mitochondrial abnormalities in AD brains.


The current therapy for management of PD is almost exclusively reliant on dopamine replacement drugs, even though they often lose their effectiveness over time and have adverse effects. In addition, this class of drugs does not slow the underlying degeneration in the SN but, rather, adds to the oxidative burden. Broader options for therapy based on our knowledge of PD pathogenesis have been anticipated. A number of studies now show that mitochondrial abnormalities and subsequent oxidative imbalance play a critical role in neurodegenerative diseases. This indicates that neurodegenerative diseases could be prevented or symptoms improved by antioxidants and chelating agents. The stage is now set to critically examine the role of mitochondria and the importance of oxidative imbalance in the pathogenesis of neurodegenerative disease.

October 16, 2002
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Citation: O. Ogawa, X. Zhu, G. Perry, M. A. Smith, Mitochondrial Abnormalities and Oxidative Imbalance in Neurodegenerative Disease. Science's SAGE KE (16 October 2002),;2002/41/pe16

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