Melatonin prevents age-related mitochondrial dysfunction in rat brain via cardiolipin protection.
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.
SourceAvailable from: onlinelibrary.wiley.com[Show abstract] [Hide abstract]
ABSTRACT: Melatonin (N-acetyl-5-methoxytryptamine), an indoleamine produced in many organs including the pineal gland, was initially characterized as a hormone primarily involved in circadian regulation of physiological and neuroendocrine function. Subsequent studies found that melatonin and its metabolic derivatives possess strong free radical scavenging properties. These metabolites are potent antioxidants against both ROS (reactive oxygen species) and RNS (reactive nitrogen species). The mechanisms by which melatonin and its metabolites protect against free radicals and oxidative stress include direct scavenging of radicals and radical products, induction of the expression of antioxidant enzymes, reduction of the activation of pro-oxidant enzymes, and maintenance of mitochondrial homeostasis. In both in vitro and in vivo studies, melatonin has been shown to reduce oxidative damage to lipids, proteins and DNA under a very wide set of conditions where toxic derivatives of oxygen are known to be produced. Although the vast majority of studies proved the antioxidant capacity of melatonin and its derivatives, a few studies using cultured cells found that melatonin promoted the generation of ROS at pharmacological concentrations (μM to mM range) in several tumor and non-tumor cells; thus, melatonin functioned as a conditional pro-oxidant. Mechanistically, melatonin may stimulate ROS production through its interaction with calmodulin. Also, melatonin may interact with mitochondrial complex III or mitochondrial transition pore to promote ROS production. Whether melatonin functions as a pro-oxidant under in vivo conditions is not well documented; thus, whether the reported in vitro pro-oxidant actions come into play in live organisms remains to be established.This article is protected by copyright. All rights reserved.Journal of Pineal Research 07/2014; DOI:10.1111/jpi.12162 · 7.81 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Aging is accompanied by mitochondrial dysfunction related with lowering of the respiratory complex activity and decrease of ATP synthesis, as well as by an enhancement of oxidative stress and increased sensitivity to mitochondrial permeability transition pore (mPTP) opening in mitochondral triggering the programmed cell death. In the present work we studied the effect of natural antioxidant (melatonin) on parameters of mPTP detected in non-synaptic mitochondria isolated from the brain of young and old rats (3 and 18 months, resp.) with different melatonin treatments; namely, melatonin was either directly applied to the mitochondrial suspension or chronically administered to rats with drinking water. The data obtained have shown that mitochondria isolated from brain of old rats were more susceptive to induction of mPTP. Melatonin added directly to suspension of brain mitochondria isolated from young rats demonstrated a proapoptotic effect. A prolonged chronical treatment with melatonin of old rats produced an anti-apoptotic protective effect. Non-synaptic mitochondria isolated from the brain of old rats treated with melatonin were more resistant to the mPTP opening and demonstrated the activation of respiration of mitochondria as compared to the untreated rats.Biochemistry (Moscow) Supplement Series A Membrane and Cell Biology 10/2013; DOI:10.1134/S1990747813040053