ReviewMelatonin and mitochondrial dysfunction in the central nervous system
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 (O2−) 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.
References (126)
- et al.
Effect of melatonin implants on gonadal weights and pineal gland fine structure of the golden hamster
Tissue Cell
(1977) Therapeutic approaches to mitochondrial dysfunction in Parkinson's disease
Parkinsonism Relat. Disord.
(2009)- et al.
Mitochondrial involvement in Alzheimer's disease
Biochim. Biophys. Acta
(1999) - et al.
The basic physiology and pathophysiology of melatonin
Sleep Med. Rev.
(2005) - et al.
Mild cognitive impairment
Lancet
(2006) - et al.
Cause and consequence: mitochondrial dysfunction initiates and propagates neuronal dysfunction, neuronal death and behavioral abnormalities in age-associated neurodegenerative diseases
Biochim. Biophys. Acta
(2010) Mitochondria—a nexus for aging, calorie restriction, and sirtuins?
Cell
(2008)- et al.
Melatonin—a pleiotropic, orchestrating regulator molecule
Prog. Neurobiol.
(2011) - et al.
Modulation of mitochondrial calcium as a pharmacological target for Alzheimer's disease
Ageing Res. Rev.
(2010) - et al.
Melatonin attenuates amyloid beta25–35-induced apoptosis in mouse microglial BV2 cells
Neurosci. Lett.
(2005)
Renal toxicity of the carcinogen delta-aminolevulinic acid: antioxidant effects of melatonin
Cancer Lett.
Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist
Neuropharmacology
Melatonin inhibits amphetamine-induced increase in alpha-synuclein and decrease in phosphorylated tyrosine hydroxylase in SK-N-SH cells
Neurosci. Lett.
Nocturnal 6-sulfatoxymelatonin excretion in insomnia and its relation to the response to melatonin replacement therapy
Am. J. Med.
Mitochondrial calcium and the permeability transition in cell death
Biochim. Biophys. Acta
Mechanism of the peroxidase activity of Cu, Zn superoxide dismutase
Free Radic. Biol. Med.
Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study
Lancet
A single blind, placebo controlled, across groups dose escalation study of the safety, tolerability, pharmacokinetics and pharmacodynamics of the melatonin analog beta-methyl-6-chloromelatonin
Life Sci.
Rhythms of glutathione peroxidase and glutathione reductase in brain of chick and their inhibition by light
Neurochem. Int.
Chronic melatonin therapy fails to alter amyloid burden or oxidative damage in old Tg2576 mice: implications for clinical trials
Brain Res.
Mitochondria, oxygen free radicals, disease and ageing
Trends Biochem. Sci.
Melatonin agonist tasimelteon (VEC-162) for transient insomnia after sleep-time shift: two randomised controlled multicentre trials
Lancet
Mitochondrial involvement in Parkinson's disease, Huntington's disease, hereditary spastic paraplegia and Friedreich's ataxia
Biochim. Biophys. Acta
Protective effect of melatonin against the 1-methyl-4-phenylpyridinium-induced inhibition of complex I of the mitochondrial respiratory chain
J. Pineal Res.
Melatonin-mitochondria interplay in health and disease
Curr. Top. Med. Chem.
A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis
Proc. Natl. Acad. Sci. U. S. A.
Direct inhibition of the mitochondrial permeability transition pore: a possible mechanism responsible for anti-apoptotic effects of melatonin
FASEB J.
Neurohormone melatonin prevents cell damage: effect on gene expression for antioxidant enzymes
FASEB J.
Melatonin as a cytoskeletal modulator: implications for cell physiology and disease
J. Pineal Res.
Alzheimer's proteins, oxidative stress, and mitochondrial dysfunction interplay in a neuronal model of Alzheimer's disease
Int. J. Alzheimers Dis.
Assessing mitochondrial dysfunction in cells
Biochem. J.
Binding of melatonin to human and rat plasma proteins
Endocrinology
Clinical aspects of melatonin intervention in Alzheimer's disease progression
Curr. Neuropharmacol.
The modulatory role of melatonin on immune responsiveness
Curr. Opin. Investig. Drugs
Interactions of melatonin with membrane models: portioning of melatonin in AOT and lecithin reversed micelles
J. Pineal Res.
Melatonin treatment normalizes plasma pro-inflammatory cytokines and nitrosative/oxidative stress in patients suffering from Duchenne muscular dystrophy
J. Pineal Res.
Melatonin preserves longevity protein (sirtuin 1) expression in the hippocampus of total sleep-deprived rats
J. Pineal Res.
Melatonin attenuates kainic acid-induced neurotoxicity in mouse hippocampus via inhibition of autophagy and alpha-synuclein aggregation
J. Pineal Res.
Mitochondrial dysfunction, metabolic deficits, and increased oxidative stress in Huntington's disease
Chang Gung Med. J.
Role of mitochondrial amyloid-beta in Alzheimer's disease
J. Alzheimers Dis.
Protective effect of melatonin on cellular energy depletion mediated by peroxynitrite and poly (ADP-ribose) synthetase activation in a non-septic shock model induced by zymosan in the rat
J. Pineal Res.
Stimulatory effects of melatonin on ependymal epithelium of choroid plexuses in golden hamsters
J. Neural Transm.
Mitochondrial disorders in the nervous system
Annu. Rev. Neurosci.
Differential effects of melatonin on amyloid-beta peptide 25–35-induced mitochondrial dysfunction in hippocampal neurons at different stages of culture
J. Pineal Res.
Melatonin treatment restores mitochondrial function in Alzheimer's mice: a mitochondrial protective role of melatonin membrane receptor signaling
J. Pineal Res.
International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors
Pharmacol. Rev.
Antiinflammatory activity of melatonin in central nervous system
Curr. Neuropharmacol.
Cytochrome P450 isoforms involved in melatonin metabolism in human liver microsomes
Eur. J. Clin. Pharmacol.
Melatonin alleviates behavioral deficits associated with apoptosis and cholinergic system dysfunction in the APP 695 transgenic mouse model of Alzheimer's disease
J. Pineal Res.
Cited by (84)
Doxorubicin induced cardio toxicity through sirtuins mediated mitochondrial disruption
2022, Chemico-Biological InteractionsMelatonin as a promising modulator of aging related neurodegenerative disorders: Role of microRNAs
2021, Pharmacological ResearchEffect of melatonin administration on the PER1 and BMAL1 clock genes in patients with Parkinson's disease
2020, Biomedicine and PharmacotherapyMelatonin: A review of its potential functions and effects on neurological diseases
2020, Revue NeurologiqueMyalgic encephalomyelitis/chronic fatigue syndrome: From pathophysiological insights to novel therapeutic opportunities
2019, Pharmacological Research