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.

Melatonin: A Potential Anti-Oxidant Therapeutic Agent for Mitochondrial Dysfunctions and Related Disorders

“…158 Melatonin also counteracted the oxidative damage to the mitochondrial membranes of the tissues like brain during aging since it prevented rigidity in the mitochondrial membrane and preserved the content and structural integrity of cardiolipin molecules. 159 Recently it has been also shown not only this melatonin can also avert the age induced in situ mitochondrial dysfunctions in smooth muscle cells which in turn has effects on their contractility and metabolism. 160 Melatonin has been reported to protect the mitochondria by preventing cardiolipin oxidation which would otherwise promote the mitochondrial transition pore opening (MPTP), resulting in cell death.…”

“…159 The effect of melatonin in the reduction of nitrosative stress has been amply studied in animal models of sepsis. Experimentally it has been proved that increase of iNOS expression was more pronounced in aged rats than young rats, but melatonin was able to reduce the expression to the same levels in both groups.…”

Melatonin as a stabilizer of mitochondrial function: role in diseases and aging

“…This phenomenon negatively impacts the structural properties (membrane fluidity and permeability) and function (respiration and oxidative phosphorylation) of the mitochondrial membrane, leading to cellular dysfunction and even cell death (Paradies et al, 2010). Some studies show that melatonin, at micromolar concentrations, would prevent the oxidation/depletion of CL (Petrosillo et al, 2006(Petrosillo et al, , 2008.…”

Melatonin and mitochondria in aging

“…Various parameters related to mitochondrial bioenergetics in rat brain tissue, including complex I activity, rate of state 3 respiration, mitochondrial hydrogen peroxide production, and membrane potential, mitochondrial content of normal and oxidized cardiolipin, are significantly altered with aging; melatonin treatment was found to completely prevent these age-related alterations. In summary, there is a decline of mitochondrial bioenergetic functions in brain with aging; melatonin treatment is beneficial since it prevents deterioration of essential mitochondrial processes (Petrosillo et al, 2008). Dong et al (2010) reported that melatonin increases mitochondrial membrane potential, ATP concentration and the activity of complexes I and IV in senescent hippocampal neurons.…”