Elsevier

Hormones and Behavior

Volume 63, Issue 2, February 2013, Pages 322-330
Hormones and Behavior

Review
Melatonin and mitochondrial dysfunction in the central nervous system

https://doi.org/10.1016/j.yhbeh.2012.02.020Get rights and content

Abstract

This article is part of a Special Issue "Hormones & Neurotrauma".

Cell death and survival are critical events for neurodegeneration, mitochondria being increasingly seen as important determinants of both. Mitochondrial dysfunction is considered a major causative factor in Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). Increased free radical generation, enhanced mitochondrial inducible nitric oxide (NO) synthase activity and NO production, and disrupted electron transport system and mitochondrial permeability transition, have all been involved in impaired mitochondrial function. Melatonin, the major secretory product of the pineal gland, is an antioxidant and an effective protector of mitochondrial bioenergetic function. Both in vitro and in vivo, melatonin was effective to prevent oxidative stress/nitrosative stress-induced mitochondrial dysfunction seen in experimental models of AD, PD and HD. These effects are seen at doses 2–3 orders of magnitude higher than those required to affect sleep and circadian rhythms, both conspicuous targets of melatonin action. Melatonin is selectively taken up by mitochondria, a function not shared by other antioxidants. A limited number of clinical studies indicate that melatonin can improve sleep and circadian rhythm disruption in PD and AD patients. More recently, attention has been focused on the development of potent melatonin analogs with prolonged effects which were employed in clinical trials in sleep-disturbed or depressed patients in doses considerably higher than those employed for melatonin. In view that the relative potencies of the analogs are higher than that of the natural compound, clinical trials employing melatonin in the range of 50–100 mg/day are needed to assess its therapeutic validity in neurodegenerative disorders.

Highlights

► Mitochondrial dysfunction is an important determinant of neurodegeneration. ► Increased free radicals and disrupted electron transport and permeability transition are involved. ► Melatonin is an antioxidant and an effective protector of mitochondrial bioenergetics. ► Melatonin improves sleep and circadian rhythm disruption in patients.

Introduction

Cell death and survival are critical events in neurodegeneration, and mitochondria are increasingly seen as important determinants of both. Abnormalities in mitochondrial functions such as defects in the electron transport chain (ETC)/oxidative phosphorylation (OXPHOS) system and ATP production have been suggested as the primary causative factors in the pathogenesis of neurodegenerative disorders (Beal, 2009, DiMauro and Schon, 2008, Rezin et al., 2009, Rollins et al., 2009, Schon et al., 2010). Mitochondria act as energy suppliers and signaling mediators in the capacity of the cells to produce energy from atmospheric oxygen. Electrons from metabolic substrates are transferred via the ETC to molecular oxygen (O2), giving rise to a H+ electrochemical gradient whose energy is used to synthesize ATP (Brand and Nicholls, 2011).

Mitochondrial dysfunction underlies neurodegenerative diseases of different etiologies, including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). Generally these age-related disorders share mitochondrial dysfunction, oxidative/nitrosative stress and increased apoptosis in different areas of the brain. In the case of AD, decreases in mRNA expression of mitochondrial DNA (mtDNA) encoding cytochrome oxidase subunit II have been reported (Bonilla et al., 1999). Aggregated β-amyloid (Aβ) generates reactive oxygen species (ROS) that produce neuronal death by damage of neuronal membrane lipids, proteins and nucleic acids. Protection from Aβ toxicity by melatonin was observed, especially at the mitochondrial level (Dragicevic et al., 2011, Olcese et al., 2009). This is the basis for the use of an antioxidant like melatonin in AD patients (see for ref. Cardinali et al., 2010).

Mitochondrial involvement in PD is suggested by deficiencies in components of the ETC like Complex (C)-I in substantia nigra with a parallel reduction in reduced glutathione (GSH) levels, indicating the existence of oxidative stress (Navarro and Boveris, 2010). In platelets of PD patients C-I is also decreased, and in some cases is accompanied by C-II, C-III and C-IV deficiencies. Studies with cybrids have shown that alterations in C-I is due to a defect in the mtDNA (Navarro and Boveris, 2010). This defect is accompanied by an alteration in the expression of C-IV activity and a reduced H+ electrochemical gradient, which lowers the apoptotic threshold. Mitochondrial involvement in the pathology of PD has been genetically supported by the finding in early-onset Parkinsonism of mutations in DNA polymerase γ, which is the only DNA polymerase present in mitochondria and necessary for mtDNA synthesis (Luoma et al., 2004).

In the case of HD, deficiencies in the activity of C-II, C-III and C-IV in caudate and to a lesser extent in putamen of patients have been reported (Schapira, 1999). In mitochondria from frontal and temporal lobes of HD patients a mtDNA deletion was found (Horton et al., 1995).

Enhanced production of ROS and possibly accumulation of mtDNA mutations in post mitotic cells are contributory factors in neurodegeneration. Mitochondria not only generate ROS/reactive nitrogen species (RNS) but are also the main target for their actions (Raha and Robinson, 2000). As a result, damage occurs in the mitochondrial respiratory chain, producing further increases in free radical generation and leading ultimately to a vicious cycle (Genova et al., 2004).

During the last decade a number of studies have demonstrated that melatonin plays an effective role in regulating mitochondrial homeostasis (see for ref. Acuña Castroviejo et al., 2011, Srinivasan et al., 2011c). In addition to being a free radical scavenger, melatonin reduces nitric oxide (NO) generation within mitochondria. It maintains the electron flow, the efficiency of OXPHOS, ATP production, the bioenergetic function of the cell and mitochondrial biogenesis by regulating respiratory complex activities, Ca2+ influx and the mitochondrial permeability transition (mPT). This article summarizes the several mechanisms through which melatonin can exert neuroprotective actions in neurodegenerative disorders like AD, PD and HD.

Section snippets

Mitochondrial function and free radical generation

The primary function of mitochondria is to generate ATP within the cell through the ETC resulting in OXPHOS. Mitochondrial energy production requires the coordination of several sequential steps tightly interconnected. Even under normal conditions, 1–2% of electron flux is the consequence of the incomplete reduction of O2, leading to the production of superoxide anion radical (O2radical dot) that is subsequently converted into hydrogen peroxide (H2O2). Hence, the mitochondria are the main source of ROS

Basic physiology of melatonin

Melatonin is the major secretory product of the pineal gland released every day at night. In all mammals, circulating melatonin is synthesized primarily in the pineal gland (Claustrat et al., 2005). In addition, melatonin is also locally synthesized in various cells, tissues and organs including lymphocytes, bone marrow, the thymus, the gastrointestinal tract, skin and the eyes, where it plays either an autocrine or paracrine role (see for ref. Hardeland et al., 2011).

Both in animals and in

Melatonin and mitochondrial function

According to Acuña Castroviejo et al. (2011) a role of melatonin in mitochondrial homeostasis seems warranted. Melatonin is a powerful scavenger of ROS and RNS and naturally acts on mitochondria, the site with the highest ROS/RNS production into the cell. Melatonin improves the GSH redox cycling and increases GSH content by stimulating its synthesis in the cytoplasm, mitochondria depending on the GSH uptake from cytoplasm to maintain the GSH redox cycling. Lastly, melatonin exerts important

Melatonin and mitochondrial dysfunction in AD

Several recent studies have supported the involvement of mitochondrial ROS and RNS production and abnormal mitochondrial function in the pathophysiology of AD (Bobba et al., 2010, Galindo et al., 2010, Manczak et al., 2010, Massaad et al., 2009, Muller et al., 2010, Santos et al., 2010, Trancikova et al., in press). AD is characterized by extracellular senile plaques of aggregated β-amyloid (Aβ) and intracellular neurofibrillary tangles that contain hyperphosphorylated tau protein. The

Melatonin and mitochondrial dysfunction in PD

PD is a neurodegenerative disorder with a multifactorial etiology, mainly characterized by the death of dopaminergic neurons in the substantia nigra pars compacta and by the formation of Lewy bodies. The initiating factor in PD is still unknown. The possible involvement of an increased release of free radicals has been entertained in view of enhanced signs of oxidative stress found in the brain of PD patients (Gibson et al., 2010).

A reduced C-I activity in the substantia nigra pars compacta and

Melatonin and mitochondrial dysfunction in HD

HD is a neurodegenerative disorder that leads to ataxia, chorea and dementia. It may be produced by a genomic alteration in the DNA encoding huntingtin, a protein of unknown function but associated with increased apoptosis. Lesions in HD include predominantly the γ-aminobutyric acid containing neurons of the caudate nucleus (Schapira, 1999). Mitochondrial dysfunction occurs in HD (Chen, 2011). A mtDNA deletion (mtDNA4977) was found in HD patients particularly in frontal and temporal lobes but

Melatonin and its analogs as pharmaceutical tools

As melatonin exhibits both hypnotic and chronobiotic properties, it has been therapeutically used for treatment of age-related insomnia as well as of other primary and secondary insomnia (Leger et al., 2004, Zhdanova et al., 2001). A recent consensus of the British Association for Psychopharmacology on evidence-based treatment of insomnia, parasomnia and circadian rhythm sleep disorders concluded that melatonin is the first choice treatment when a hypnotic is indicated in patients over 55 years (

Conclusions

Abnormal mitochondrial function, decreased respiratory enzyme complex activities, increased electron leakage and mPT, and increased Ca2+ entry have all been shown to play a role in the pathophysiology of neurodegenerative disorders. In various neurodegenerative diseases, such as AD, PD or HD, mitochondrial changes are not only observed at the level of ETC dysfunction, electron leakage and oxidative, nitrosative or nitrative damage, but also in a disturbed balance between mitochondrial fusion

Acknowledgments

Studies in authors' laboratories were supported by grants from the Agencia Nacional de Promoción Científica y Tecnológica, Argentina and the University of Buenos Aires. DPC is a Research Career Awardee from the Argentine Research Council (CONICET) and Professor Emeritus, University of Buenos Aires. ESP and PS are Research Career Awardees from CONICET.

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