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February 2006

Biochemical functions of coenzyme Q10.

Coenzyme Q is well defined as a crucial component of the oxidative phosphorylation process in mitochondria which converts the energy in carbohydrates and fatty acids into ATP to drive cellular machinery and synthesis. New roles for coenzyme Q in other cellular functions are only becoming recognized. The new aspects have developed from the recognition that coenzyme Q can undergo oxidation/reduction reactions in other cell membranes such as lysosomes. Golgi or plasma membranes. In mitochondria and lysosomes, coenzyme Q undergoes reduction/oxidation cycles during which it transfers protons across the membrane to form a proton gradient. The presence of high concentrations of quinol in all membranes provides a basis for antioxidant action either by direct reaction with radicals or by regeneration of tocopherol and ascorbate. Evidence for a function in redox control of cell signaling and gene expression is developing from studies on coenzyme Q stimulation of cell growth, inhibition of apoptosis, control of thiol groups, formation of hydrogen peroxide and control of membrane channels. Deficiency of coenzyme Q has been described based on failure of biosynthesis caused by gene mutation, inhibition of biosynthesis by HMG coA reductase inhibitors (statins) or for unknown reasons in ageing and cancer. Correction of deficiency requires supplementation with higher levels of coenzyme Q than are available in the diet.

J Am Coll Nutr. 2001 Dec;20(6):591-8

Improvement of visual functions and fundus alterations in early age-related macular degeneration treated with a combination of acetyl-L-carnitine, n-3 fatty acids, and coenzyme Q10.

The aim of this randomized, double-blind, placebo-controlled clinical trial was to determine the efficacy of a combination of acetyl-L-carnitine, n-3 fatty acids, and coenzyme Q10 (Phototrop) on the visual functions and fundus alterations in early age-related macular degeneration (AMD). One hundred and six patients with a clinical diagnosis of early AMD were randomized to the treated or control groups. The primary efficacy variable was the change in the visual field mean defect (VFMD) from baseline to 12 months of treatment, with secondary efficacy parameters: visual acuity (Snellen chart and ETDRS chart), foveal sensitivity as measured by perimetry, and fundus alterations as evaluated according to the criteria of the International Classification and Grading System for AMD. The mean change in all four parameters of visual functions showed significant improvement in the treated group by the end of the study period. In addition, in the treated group only 1 out of 48 cases (2%) while in the placebo group 9 out of 53 (17%) showed clinically significant (>2.0 dB) worsening in VFMD (p = 0.006, odds ratio: 10.93). Decrease in drusen-covered area of treated eyes was also statistically significant as compared to placebo when either the most affected eyes (p = 0.045) or the less affected eyes (p = 0.017) were considered. These findings strongly suggested that an appropriate combination of compounds which affect mitochondrial lipid metabolism, may improve and subsequently stabilize visual functions, and it may also improve fundus alterations in patients affected by early AMD.

Ophthalmologica. 2005 May-Jun;219(3):154-66

Coenzyme Q10 for prevention of anthracycline-induced cardiotoxicity.

Preclinical and clinical studies suggest that anthracycline-induced cardiotoxicity can be prevented by administering coenzyme Q10 during cancer chemotherapy that includes drugs such as doxorubicin and daunorubicin. Studies further suggest that coenzyme Q10 does not interfere with the antineoplastic action of anthracyclines and might even enhance their anticancer effects. Preventing cardiotoxicity might allow for escalation of the anthracycline dose, which would further enhance the anticancer effects. Based on clinical investigation, although limited, a cumulative dose of doxorubicin of up to 900 mg/m2, and possibly higher, can be administered safely during chemotherapy as long as coenzyme Q10 is administered concurrently. The etiology of the dose-limiting cardiomyopathy that is induced by anthracyclines can be explained by irreversible damage to heart cell mitochondria, which differ from mitochondria of other cells in that they possess a unique enzyme on the inner mitochondrial membrane. This enzyme reduces anthracyclines to their semiquinones, resulting in severe oxidative stress, disruption of mitochondrial energetics, and irreversible damage to mitochondrial DNA. Damage to mitochondrial DNA blocks the regenerative capability of the organelle and ultimately leads to apoptosis or necrosis of myocytes. Coenzyme Q10, an essential component of the electron transport system and a potent intracellular antioxidant, appears to prevent damage to the mitochondria of the heart, thus preventing the development of anthracycline-induced cardiomyopathy.

Integr Cancer Ther. 2005 Jun;4(2):110-30

Role of mitochondria in neuronal cell death induced by oxidative stress; neuroprotection by Coenzyme Q10.

Neuronal cells depend on mitochondrial oxidative phosphorylation for most of their energy needs and therefore are at a particular risk for oxidative stress. Mitochondria play an important role in energy production and oxidative stress-induced apoptosis. In the present study, we have demonstrated that external oxidative stress induces mitochondrial dysfunction leading to increased ROS generation and ultimately apoptotic cell death in neuronal cells. Furthermore, we have investigated the role of Coenzyme Q10 as a neuroprotective agent. Coenzyme Q10 is a component of the mitochondrial respiratory chain and a potent antioxidant. Our results indicate that total cellular ROS generation was inhibited by Coenzyme Q10. Further, pre-treatment with Coenzyme Q10 maintained mitochondrial membrane potential during oxidative stress and reduced the amount of mitochondrial ROS generation. Our study suggests that water-soluble Coenzyme Q10 acts by stabilizing the mitochondrial membrane when neuronal cells are subjected to oxidative stress. Therefore, Coenzyme Q10 has the potential to be used as a therapeutic intervention for neurodegenerative diseases.

Neurobiol Dis. 2005 Apr;18(3):618-27


Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study.

BACKGROUND: Antioxidants may protect the aging brain against oxidative damage associated with pathological changes of Alzheimer disease (AD). OBJECTIVE: To examine the relationship between antioxidant supplement use and risk of AD. DESIGN: Cross-sectional and prospective study of dementia. Elderly (65 years or older) county residents were assessed in 1995 to 1997 for prevalent dementia and AD, and again in 1998 to 2000 for incident illness. Supplement use was ascertained at the first contact. SETTING: Cache County, Utah. PARTICIPANTS: Among 4,740 respondents (93%) with data sufficient to determine cognitive status at the initial assessment, we identified 200 prevalent cases of AD. Among 3,227 survivors at risk, we identified 104 incident AD cases at follow-up. MAIN OUTCOME MEASURE: Diagnosis of AD by means of multistage assessment procedures. RESULTS: Analyses of prevalent and incident AD yielded similar results. Use of vitamin E and C (ascorbic acid) supplements in combination was associated with reduced AD prevalence (adjusted odds ratio, 0.22; 95% confidence interval, 0.05-0.60) and incidence (adjusted hazard ratio, 0.36; 95% confidence interval, 0.09-0.99). A trend toward lower AD risk was also evident in users of vitamin E and multivitamins containing vitamin C, but we saw no evidence of a protective effect with use of vitamin E or vitamin C supplements alone, with multivitamins alone, or with vitamin B-complex supplements. CONCLUSIONS: Use of vitamin E and vitamin C supplements in combination is associated with reduced prevalence and incidence of AD. Antioxidant supplements merit further study as agents for the primary prevention of AD.

Arch Neurol. 2004 Jan;61(1):82-8

Free radicals and aging.

Aging is characterized by decrements in maximum function and accumulation of mitochondrial DNA mutations, which are best observed in organs such as the brain that contain post-mitotic cells. Oxygen radicals are increasingly considered responsible for part of these aging changes. Comparative studies of animals with different aging rates have shown that the rate of mitochondrial oxygen radical generation is directly related to the steady-state level of oxidative damage to mitochondrial DNA and is inversely correlated with maximum longevity in higher vertebrates. The degree of unsaturation of tissue fatty acids also correlates inversely with maximum longevity. These are the two known traits connecting oxidative stress with aging. Furthermore, caloric restriction, which decreases the rate of aging, proportionately decreases mitochondrial oxygen radical generation, especially at complex I. These findings are reviewed, highlighting the results obtained in the brain.

Trends Neurosci. 2004 Oct;27(10):595-600

Aging and oxidative stress.

The scientific establishment has been discussing the relationship between aging and oxidative stress for quite some time now. While we are still far from a general agreement about this subject, there is an impressive amount of data collected that can be used to draw a compelling picture of the events that take place during the human aging process and their correlation with the oxidant status of the organism. In this review, we bring forth the results of some key studies that can help to elucidate the aging-oxidative stress puzzle, as well as to explain which are the fundamental events in this interplay and why their causal relationships remain so elusive. We also put forward here data on the systemic oxidative stress status of a group of 503 healthy human subjects. The data consist of the plasma levels of TBARS and of the nutritional antioxidants, alpha-tocopherol, beta-carotene, and ascorbic acid, and of the activity of the antioxidant enzymes, Cu, Zn-superoxide dismutase, catalase and glutathione peroxidase, of red blood cells. The data indicate that a moderate situation of oxidative stress gradually develops during human aging.

Mol Aspects Med. 2004 Feb-Apr;25(1-2):5-16

Mitochondrial DNA repair and aging.

The mitochondrial electron transport chain plays an important role in energy production in aerobic organisms and is also a significant source of reactive oxygen species that damage DNA, RNA and proteins in the cell. Oxidative damage to the mitochondrial DNA is implicated in various degenerative diseases, cancer and aging. The importance of mitochondrial ROS in age-related degenerative diseases is further strengthened by studies using animal models, Caenorhabditis elegans, Drosophila and yeast. Research in the last several years shows that mitochondrial DNA is more susceptible to various carcinogens and ROS when compared to nuclear DNA. DNA damage in mammalian mitochondria is repaired by base excision repair (BER). Studies have shown that mitochondria contain all the enzymes required for BER. Mitochondrial DNA damage, if not repaired, leads to disruption of electron transport chain and production of more ROS. This vicious cycle of ROS production and mtDNA damage ultimately leads to energy depletion in the cell and apoptosis.

Mutat Res. 2002 Nov 30;509(1-2):127-51

Lutein, but not alpha-tocopherol, supplementation improves visual function in patients with age-related cataracts: a 2-y double-blind, placebo-controlled pilot study.

OBJECTIVE: We investigated the effect of long-term antioxidant supplementation (lutein and alpha-tocopherol) on serum levels and visual performance in patients with cataracts. METHODS: Seventeen patients clinically diagnosed with age-related cataracts were randomized in a double-blind study involving dietary supplementation with lutein (15 mg; n = 5), alpha-tocopherol (100 mg; n = 6), or placebo (n = 6), three times a week for up to 2 y. Serum carotenoid and tocopherol concentrations were determined with quality-controlled high-performance liquid chromatography, and visual performance (visual acuity and glare sensitivity) and biochemical and hematologic indexes were monitored every 3 mo throughout the study. Changes in these parameters were assessed by General Linear Model (GLM) repeated measures analysis. RESULTS: Serum concentrations of lutein and alpha-tocopherol increased with supplementation, although statistical significance was reached only in the lutein group. Visual performance (visual acuity and glare sensitivity) improved in the lutein group, whereas there was a trend toward the maintenance of and decrease in visual acuity with alpha-tocopherol and placebo supplementation, respectively. No significant side effects or changes in biochemical or hematologic profiles were observed in any of the subjects during the study. CONCLUSIONS: Visual function in patients with age-related cataracts who received the lutein supplements improved, suggesting that a higher intake of lutein, through lutein-rich fruit and vegetables or supplements, may have beneficial effects on the visual performance of people with age-related cataracts.

Nutrition. 2003 Jan;19(1):21-4

Carotenoid and vitamin E status are associated with indicators of sarcopenia among older women living in the community.

BACKGROUND AND AIMS: Oxidative stress may play a role in the pathogenesis of sarcopenia, and the relationship between dietary antioxidants and sarcopenia needs further elucidation. The aim was to determine whether dietary carotenoids and alpha-tocopherol are associated with sarcopenia, as indicated by low grip, hip, and knee strength. METHODS: Cross-sectional analyses were conducted on 669 non-disabled to severely disabled community-dwelling women aged 70 to 79 who participated in the Women¹s Health and Aging Studies. Plasma carotenoids and alpha-tocopherol were measured. Grip, hip, and knee strength were measured, and low strength was defined as the lowest tertile of each strength measure. RESULTS: Higher plasma concentrations of alpha-carotene, beta-carotene, beta-cryptoxanthin, and lutein/zeaxanthin were associated with reduced risk of low grip, hip, and knee strength. After adjusting for potential confounding factors such as age, race, smoking, cardiovascular disease, arthritis, and plasma interleukin-6 concentrations, there was an independent association for women in the highest compared with the lowest quartile of total carotenoids with low grip strength [Odds Ratios (OR) 0.34, 95% Confidence Interval (CI) 0.20-0.59], low hip strength (OR 0.28, 95% CI 0.16-0.48), and low knee strength (OR 0.45, 95% CI 0.27-0.75), and there was an independent association for women in the highest compared with the lowest quartile of alpha-tocopherol with low grip strength (OR 0.44, 95% CI 0.24-0.78) and low knee strength (OR 0.52, 95% CI 0.29-0.95). CONCLUSIONS: Higher carotenoid and alpha-tocopherol status were independently associated with higher strength measures. These data support the hypothesis that oxidative stress is associated with sarcopenia in older adults, but further longitudinal and interventional studies are needed to establish causality.

Aging Clin Exp Res. 2003 Dec;15(6):482-7

Delaying brain mitochondrial decay and aging with mitochondrial antioxidants and metabolites.

Mitochondria decay with age due to the oxidation of lipids, proteins, RNA, and DNA. Some of this decay can be reversed in aged animals by feeding them the mitochondrial metabolites acetylcarnitine and lipoic acid. In this review, we summarize our recent studies on the effects of these mitochondrial metabolites and mitochondrial antioxidants (alpha-phenyl-N-t-butyl nitrone and N-t-butyl hydroxylamine) on the age-associated mitochondrial decay of the brain of old rats, neuronal cells, and human diploid fibroblast cells. In feeding studies in old rats, these mitochondrial metabolites and antioxidants improve the age-associated decline of ambulatory activity and memory, partially restore mitochondrial structure and function, inhibit the age-associated increase of oxidative damage to lipids, proteins, and nucleic acids, elevate the levels of antioxidants, and restore the activity and substrate binding affinity of a key mitochondrial enzyme, carnitine acetyltransferase. These mitochondrial metabolites and antioxidants protect neuronal cells from neurotoxin- and oxidant-induced toxicity and oxidative damage; delay the normal senescence of human diploid fibroblast cells, and inhibit oxidant-induced acceleration of senescence. These results suggest a plausible mechanism: with age, increased oxidative damage to proteins and lipid membranes, particularly in mitochondria, causes a deformation of structure of enzymes, with a consequent decrease of enzyme activity as well as substrate binding affinity for their substrates; an increased level of substrate restores the velocity of the reaction and restores mitochondrial function, thus delaying mitochondrial decay and aging. This loss of activity due to coenzyme or substrate binding appears to be true for a number of other enzymes as well, including mitochondrial complex III and IV.

Ann N Y Acad Sci. 2002 Apr;959:133-66

Oxidative stress, mitochondrial DNA mutation, and impairment of antioxidant enzymes in aging.

Mitochondria do not only produce less ATP, but they also increase the production of reactive oxygen species (ROS) as by-products of aerobic metabolism in the aging tissues of the human and animals. It is now generally accepted that aging-associated respiratory function decline can result in enhanced production of ROS in mitochondria. Moreover, the activities of free radical-scavenging enzymes are altered in the aging process. The concurrent age-related changes of these two systems result in the elevation of oxidative stress in aging tissues. Within a certain concentration range, ROS may induce stress response of the cells by altering expression of respiratory genes to uphold the energy metabolism to rescue the cell. However, beyond the threshold, ROS may cause a wide spectrum of oxidative damage to various cellular components to result in cell death or elicit apoptosis by induction of mitochondrial membrane permeability transition and release of apoptogenic factors such as cytochrome c. Moreover, oxidative damage and large-scale deletion and duplication of mitochondrial DNA (mtDNA) have been found to increase with age in various tissues of the human. Mitochondria act like a biosensor of oxidative stress and they enable cell to undergo changes in aging and age-related diseases. On the other hand, it has recently been demonstrated that impairment in mitochondrial respiration and oxidative phosphorylation elicits an increase in oxidative stress and causes a host of mtDNA rearrangements and deletions. Here, we review work done in the past few years to support our view that oxidative stress and oxidative damage are a result of concurrent accumulation of mtDNA mutations and defective antioxidant enzymes in human aging.

Exp Biol Med (Maywood). 2002 Oct;227(9):671-82

Mitochondrial free radical generation, oxidative stress, and aging.

Mitochondria have been described as ³the powerhouses of the cell² because they link the energy-releasing activities of electron transport and proton pumping with the energy conserving process of oxidative phosphorylation, to harness the value of foods in the form of ATP. Such energetic processes are not without dangers, however, and the electron transport chain has proved to be somewhat ³leaky.² Such side reactions of the mitochondrial electron transport chain with molecular oxygen directly generate the superoxide anion radical (O2*-), which dismutates 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 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 generated by mitochondria, or from other sites within or outside the cell, cause damage to mitochondrial components and initiate degradative processes. Such toxic reactions contribute significantly to the aging process and form the central dogma of ³The Free Radical Theory of Aging.² In this article we review current understandings of mitochondrial DNA, RNA, and protein modifications by oxidative stress and the enzymatic removal of oxidatively damaged products by nucleases and proteases. The possible contributions of mitochondrial oxidative polynucleotide and protein turnover to apoptosis and aging are explored.

Free Radic Biol Med. 2000 Aug;29(3-4):222-30

Can antioxidant diet supplementation protect against age-related mitochondrial damage?

Harman¹s free radical theory of aging and our electron-microscopic finding of an age-related mitochondrial degeneration in the somatic tissues of the insect Drosophila melanogaster as well as in the fixed postmitotic Leydig and Sertoli cells of the mouse testis led us to propose a mitochondrial theory of aging, according to which metazoan senescence may be linked to oxygen stress-injury to the genome and membranes of the mitochondria of somatic differentiated cells. These concepts attract a great deal of attention, since, according to recent work, the mitochondrial damage caused by reactive oxygen species (ROS) and concomitant decline in ATP synthesis seem to play a key role not only in aging, but also in the fundamental cellular process of apoptosis. Although diet supplementation with antioxidants has not been able to increase consistently the species-characteristic maximum life span, it results in significant extension of the mean life span of laboratory animals. Moreover, diets containing high levels of antioxidants such as vitamins C and E seem able to reduce the risk of suffering age-related immune dysfunctions and arteriosclerosis. Presently, the focus of age-related antioxidant research is on compounds, such as deprenyl, coenzyme Q10, alpha-lipoic acid, and the glutathione-precursors thioproline and N-acetylcysteine, which may be able to neutralize the ROS at their sites of production in the mitochondria. Diet supplementation with these antioxidants may protect the mitochondria against respiration-linked oxygen stress, with preservation of the genomic and structural integrity of these energy-producing organelles and concomitant increase in functional life span.

Ann N Y Acad Sci. 2002 Apr;959:508-16