Melatonin Prevents Age-Related Mitochondrial Dysfunction in Rat Brain Via Cardiolipin Protection

Department of Biochemistry and Molecular Biology, CNR Institute of Biomembranes and Bioenergetics, University of Bari, Bari Italy.
Rejuvenation Research (Impact Factor: 3.31). 11/2008; 11(5):935-43. DOI: 10.1089/rej.2008.0772
Source: PubMed

ABSTRACT Reactive oxygen species (ROS) are considered a key factor in brain aging process. Complex I of the mitochondrial respiration chain is an important site of ROS production and hence a potential contributor to brain functional changes with aging. Appropriate antioxidant strategies could be particularly useful to limit this ROS production and associated mitochondrial dysfunction. Melatonin has been shown to possess antioxidant properties and to reduce oxidant events in brain aging. The mechanism underlying this protective effect of melatonin is not well established. In the present study, we examined the effects of long-term treatment of aged rats with melatonin on various parameters related to mitochondrial bioenergetics in brain tissue. After isolation of mitochondria from control, aged, and melatonin-treated young and aged rats, various bioenergetic parameters were evaluated such as complex I activity, rates of state 3 respiration, mitochondrial hydrogen peroxide (H2O2) production, and membrane potential. The mitochondrial content of normal and oxidized cardiolipin was also evaluated. We found that all these mitochondrial parameters were significantly altered with aging, and that melatonin treatment completely prevented these age-related alterations. These effects appear to be due, at least in part, to melatonin's ability to preserve the content and structural integrity of cardiolipin molecules, which play a pivotal role in mitochondrial bioenergetics. The melatonin's ability to prevent complex I dysfunction and cardiolipin peroxidation was also demonstrated by in vitro experiments on brain mitochondria treated with tert-butyl hydroperoxide. In summary, this study documents a decline of mitochondrial bioenergetic functions in brain with aging and the beneficial effect of melatonin.

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    • "The beneficial actions of melatonin against aging and different diseases, including Alzheimer's disease, Parkinson's disease, epilepsy, ischemia-reperfusion and sepsis, may be explained, at least in part, by its antioxidant and free radical scavenging properties; these actions preserve the stability, integrity, function and homeostasis of cellular components, including mitochondrial membranes [132] [134] [208] [209] [210] [211] [212]. In addition, melatonin has an uncommonly low toxicity profile [95] "
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    ABSTRACT: Oxidative damage is related to aging and a wide range of human disorders. Mitochondria are in large part responsible of free radical production and they are also main targets of the attack of these toxic molecules. The resulting deleterious effects of the damage to mitochondria can be prevented by antioxidants. Melatonin is an endogenously-produced indoleamine that modulates numerous functions, including mitochondria-related functions; this results from its capacity to penetrate all morphophysiological barriers and to enter all subcellular compartments due to its amphiphilic nature. Furthermore, this indoleamine and its metabolites are powerful antioxidants and scavengers of free radical, protecting cellular membranes, the electron transport chain and mitochondrial DNA from oxidative damage. These properties may make melatonin a potent protector against a variety of free radical-related diseases. By comparison, other conventional antioxidants have less efficacy due to their limited access to the mitochondria. In recent years, research has focused on the advancement of mitochondria-targeted antioxidants, such as MitoQ (composed by the lipophilic triphenylphosphonium cation conjugated to the endogenous antioxidant coenzyme Q10) and MitoE (composed by the triphenylphosphonium cation attached to the antioxidant α-tocopherol). Mitochondria-targeted antioxidants accumulate in several hundred-fold greater concentrations within mitochondria and protect these critical organelles from oxidative damage. Melatonin also seems to be a mitochondria-targeted antioxidant and has similar protective actions as the synthetic antioxidants. Further work is required to determine the therapeutic properties of these antioxidants in ameliorating diseases related to mitochondrial dysfunction.
    Current Medicinal Chemistry 06/2015; 22(22). DOI:10.2174/0929867322666150619104143 · 3.85 Impact Factor
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    • "During normal aging and in the earlier stages of neurodegenerative disorders, the immunologically relevant changes have to be classified as low-grade inflammation and may also be regarded as, to a certain extent, atypical. Nevertheless, the evidence from studies in aging animals mostly speak for a predominantly anti-inflammatory, antioxidative and mitochondrial-protective role of melatonin (Petrosillo et al., 2008; Cheng et al., 2008; Tajes et al., 2009; Carretero et al., 2009; O ¨ ztü rk et al., 2012). Unfortunately, most of the direct evidence for antiinflammatory actions that are based on reductions of proinflammatory cytokines has been obtained in peripheral organs (Cuesta et al., 2010, 2011; Forman et al., 2010, 2011). "
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    • "The role of melatonin as a potent molecule for the suppression of oxidative stress has been investigated by many teams. Experiments have shown that melatonin can ameliorate the overproduction of reactive oxygen species generated by complex I of the mitochondrial respiration chain by way of cardiolipin, an important part of the mitochondrial inner membrane protection (Petrosillo et al. 2008). Melatonin can keep the mitochondrial membrane fluidity as it protects from lipid peroxidation and it is speculated that mitochondrial membrane protection can slow down age related degeneration (García et al. 1997, 2010). "
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    ABSTRACT: Age related neurodegenerative disorders are becoming a serious public health problem. Alzheimer's disease (AD) is a progressive disease pathologically recognizable by deposition of neurofibrillary tangles and amyloid plaques. Oxidative stress probably plays a pivotal role in AD, but despite expectations, antioxidants such as vitamin E, vitamin C, β carotene, and flavonoids have failed as effective prophylaxis and/or treatment. Melatonin, a hormone controlling circadian rhythm, is a potent terminal antioxidant. In vitro tests and animal models have established that the application of melatonin could be beneficial for the amelioration of AD progression. Unfortunately, melatonin effects in human beings are not well understood and a lot of work has still to be done. The review summarizes the basic facts about melatonin and its prospects as a treatment for AD using its hormonal and antioxidant properties.
    Journal of applied biomedicine 12/2011; 9(4):185-196. DOI:10.2478/v10136-011-0003-6 · 1.30 Impact Factor
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