Please cite this paper as:

Süzen, S., Atayik, M.C, Sirinzade, H., Entezari, B., Gurer-Orhan, H. and Cakatay, U 2022. Melatonin and Redox Homeostasis. Melatonin Research. 5, 3 (Sep. 2022), 304-324. DOI:https://doi.org/https://doi.org/10.32794/mr112500134


Review

Melatonin and redox homeostasis

Sibel Suzen1, Mehmet Can Atayik2, Hanif Sirinzade3, Bita Entezari4, Hande Gurer-Orhan4, Ufuk Çakatay5*

 1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Tandogan-06100, Ankara, Turkey

2Medical Program, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, 34098 Istanbul, Turkey

3Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Selcuk University, Keykubat Campus, 42130 Konya, Turkey

4Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Ege University, 35040 Izmir, Turkey

5Department of Medical Biochemistry, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, 34098 Istanbul, Turkey

* Correspondence: email: ufuk.cakatay@istanbul.edu.tr, Tel: +905307882131      

Running Title: Melatonin and redox homeostasis

Received:  August 16, 2022; Accepted: September 26, 2022

 

ABSTRACT

     Redox homeostasis and redox signaling are constituents of preservation of a normal physiological state. Whereas the equilibrium between oxidants and nucleophiles is conserved in redox homeostasis, oxidative stress promotes the formation of a radically altered redox state. It is known that modification of circadian clock may lead to severe alteration in redox balance. Melatonin [N-acetyl-5-methoxytryptamine, (MLT)] regulates numerous physiological functions including circadian rhythm, sleep-wake cycle, gonadal activity, redox homeostasis, neuroprotection, immune-modulation, and anticancer activity in organisms. Insufficient MLT production is closely related to development of aging process, tumorigenesis, visceral adiposity, neurodegenerative disorders, etc. Reactive oxygen species (ROS) are not intrinsically harmful or beneficial in cellular redox metabolism. Redox homeostasis is an integrative status for both of the hormetic response to ROS overproduction and subsequent redox signaling. MLT and its derivatives are traditionally classified as hormone-like substances. Their redox sensitive regulatory activity and direct interaction with intracellular ROS serve as second messenger in cell signaling. This review involves the role of redox homeostasis in the pathogenesis of age-related disorders and its relationship with MLT, therefore, targeting the circadian rhythm may propose new therapeutic approach for these disorders.

Key words: redox homeostasis, melatonin, oxidative stress, aging, neurodegenerative diseases, autophagy

 _____________________________________________________________________________________________________


​1. INTRODUCTION

     Cells preserve a stable cytosolic redox state to uphold both the oxidative bioenergetic reactions and the reductive anabolic progressions that underlie biological systems. This process promotes redox signaling and avoids oxidative damage to cellular macromolecules. Redox homeostasis is a crucial and active process that confirms the equilibrium between reducing and oxidizing reactions within cells and controls a variety of biological reactions and procedures (1).

Metabolism, redox homeostasis, circadian rhythm, and nutrition are closely related to aging. Mitochondria plays an essential role in redox homeostasis, circadian rhythm and aging (2). Mitochondria as the energy producing organelles, take place in upholding cellular homeostasis. Accumulating evidence has shown that the mitochondrion is a suitable target to combat the oxidative stress (OS) (3). Mitochondria hold their individual genome with an adjusted genetic code. It is proposed that transcription of some mitochondrial genes could be responsible for the redox potential of the mitochondrial membrane. The impacts of mitochondria on neurodegenerative and neuromuscular disorders including modifications in both nuclear (nDNA) and mitochondrial (mtDNA) DNA have been demonstrated. Metabolic disorders including diabetes, cardiovascular and neurodegenerative diseases as well as obesity and aging may implicate an exceedingly multifaceted breakdown in physiological systems, with the syndrome becoming determined if the injury cannot be restored (4).

     The suprachiasmatic nucleus (SCN) synchronizes the biological circadian rhythms, including sleep and wakefulness, temperature, nutrition, neuroendocrine and autonomic effects, with the 24 h cycle based on the environmental light/dark cycle (5).  Melatonin [N-acetyl-5-methoxytryptamine, (MLT)] is a chief biological sleep regulator in humans. A neural signal generated from the SCN prompts the production of MLT at night in the pineal gland. Besides the pineal gland, many organs and tissues have the ability to produce MLT (6). As a potent antioxidant melatonin displays its advantageous properties against OS-based macromolecular injury, counting those in which mitochondrial action is affected (7). Accumulating evidence reveals that MLT has significant roles in many metabolic functions as an anti-oxidant, anti-inflammatory and conceivably as an epigenetic regulator. The actions of MLT are primarily mediated by G-protein coupled MT1 and MT2 receptors; however, several intracellular protein and nuclear receptors also modulate these activities (8).

     MLT exhibits pleiotropic activities on mitochondria. Mitochondria are the main source of free radical production in the cells and are associated with aging progression. Mitochondria play a crucial role in apoptosis. MLT's antioxidant capability is established not only on direct radical scavenging but also with various other means (9). Furthermore, the mechanisms by which MLT and its metabolites defend against oxidants and OS involve stimulation of the expression of antioxidant enzymes, reduction of the triggering pro-oxidant enzymes, and preservation of mitochondrial homeostasis (10). The suitable pharmacokinetics of melatonin also favor its antioxidant ability. For example, MLT is rapidly absorbed after its oral administration and go through first-pass hepatic metabolism between 20 min and 2 h, then levels continue for up to 1.5 h (11).

     The role of MLT in the management of the circadian rhythm has led to investigation of MLT as a therapeutic agent of many disorders, specifically neurodegenerative and cardiovascular diseases.  It regulates various physiological functions, including sleep and circadian rhythm, neuro and cardiovascular activities, acting as powerful antioxidant and protecting tissues from lipid peroxidation, inflammation, reducing tumor growth, inducing apoptosis, and enhancing mitochondrial activity (12). Recently, MLT is found to participate in immunomodulatory, antiangiogenic, antiaging and antioxidant activities (13). Insufficient levels of MLT could escalate the possibility of neurodegeneration, aging, immunoregulation disorder, and senescence.

     Immunomodulatory activities of MLT have been extensively studied (14) with the observations either pro or anti-inflammatory effects depending on conditions (15). Under the regular and immunosuppressed conditions, MLT exhibits immune-enhancing properties. It also suppresses inflammatory reactions via non-immunological activities, such as antioxidative activity and mitochondrial functional preservation, in which melatonin promotes antioxidative process as well as decline ROS generation including NO formation (16, 17). The oxidation and inflammation have a strong connection, as the high level of OS prompts an inflammatory reaction, and ROS are the main risk factors of inflammation (18). MLT production declines with the age and the accelerated aging is associates with the MLT insufficiency (19). In fact, the relationship between MLT and aging is so strong that both extrapineal and pineal MLT are currently considered the useful biomarkers of the aging rate for organisms (20).

     Redox interactions maintain the parameters of varied biological actions, involving metabolism, cell death, differentiation and development, immune responses, circadian rhythm, etc. This review on MLT and redox homeostasis summarized some of the most current developments as to how redox homeostasis is maintained, and what roles of MLT play in this process. The relationship between MLT and OS that causing aging and neurodegenerative diseases, autophagy, aging, and MLT derivatives as antioxidant in aging and neurodegenerative disorders are also discussed.

 

2. CELLULAR REDOX HOMEOSTASIS, REACTIVE OXYGEN SPECIES

     During the evolution of the photosynthetic microorganisms about 2.4 billion years ago, reactive oxygen species (ROS) appeared as unexpected byproducts of aerobic organisms (21). The gradual accumulation of molecular oxygen into the reductive atmosphere promotes the generation of ROS (22). Enrichment of molecular oxygen to Earth's ancient atmosphere causes significant evolutionary adaptations. A wide group of electron acceptor-molecules play crucial roles in energy-yielding metabolic pathways. Enzymatic reduction of O2 yielded a several-fold increase in energy production, enabling evolution of multi-cellular organisms. More than half a century ago, Argentinian physiologist, Rebeca Gerschman and her co-workers hypothesized that free radicals are detrimental and labile products associated with oxygen poisoning (23). Each oxygen atom has two lone pair electrons in its outer obit, whereas molecular oxygen has four lone pair electrons. Stable form of molecular oxygen is found in triplet state. Triplet dioxygen has one full σ bond plus two π half-bonds. Triplet oxygen (3O2) can be defined as a form of "ground state." The ground state refers to the situation that the outer valence obit electrons are in their lowest energy configuration. Triplet state is the most stable form of oxygen molecule and able to excite to be a reactive singlet oxygen (1O2) form by spin inversion.  Singlet oxygen has one full σ and π bonds.

     The electron transport chain in mitochondria ensures a safeguard tetravalent reduction of molecular oxygen to produce water. The univalent reduction of molecular oxygen due to electron leak forms ROS (24). In aging cells, impaired electron transfer chain activity causes higher rates of electron leakage. Higher ROS levels may lead to the overaction of redox signaling pathways and this overaction promotes inflammation, cancer, cell death, and the accelerated aging phenotype (25). MLT alleviates the mitochondrial electron leakage and acts as an electron rich antioxidant to scavenge 1O2, O2∙-, O22-, and OH∙ radicals with non-equimolar reactions (26).

     The cellular redox homeostasis depends on fine-tuned balance between the formation and the removal of ROS, which regulates many physiological processes by mediating signaling pathways and facilitating the activation of redox-sensitive proteins and enzymes. However, gradual accumulation of oxidative products interferes with redox signaling events, which can damage cellular signaling pathways and subcellular integrity, and may eventually cause cellular aging and death (27). Redoxtasis depends on the sustainability of a delicate balance between electron rich and poor functional groups for a healthy physiological steady state in organisms. Electrophiles and nucleophile groups are not intrinsically harmful or protective for cell survival.  Redoxtasis is an essential feature of both the ROS-related response to challenges and subsequent feedback. While the balance between electron rich and poor species is ensured with well-tuned redoxtasis, variations in ROS formation rate induces the establishment of a new radically altered redox steady state (28). Physiological level of ROS formation may induce hormesis-related redox signaling mechanisms, whereas higher levels induce senescence or programmed cell death. The indispensable role of ROS in cell survival is closely related to the essential role of these labile molecules in cell signaling. Hormesis can be defined as ROS-induced adaptive response to the effects of a variety of low level of oxidant products that render target cells to induce resistance to higher amplitude of ROS (29). As the redox shift is rapidly changed by feedback reactions, redoxtasis is ensured by continuous signaling for production and removal of electrophiles and nucleophile groups.

     MLT and its derivatives have redox modulatory effects on ROS and reactive nitrogen species (RNS) (30). MLT-induced redox regulation may be accomplished with direct ROS scavenging, enzymatic and non-enzymatic antioxidant systems (31). Exogenous non-enzymatic antioxidants are supplied nutritionally such as vitamin A, E, C xanthophylls, polyphenols, and carotenoids (32). Whilst vitamin C acts as hydrophilic antioxidant, others such as vitamin A, E, polyphenols and carotenoids active in the hydrophobic environment (33). The direct antioxidant effects of MLT depend on its own electron-rich aromatic indole ring. Indole ring makes it a potent electron donor that can significantly reduce free radicals (34). Mechanistically, MLT-dependent prooxidant activity may increase ROS production rate through its interaction with calmodulin or interaction with mitochondrial complex III under certain conditions (35). Since MLT, its metabolites and synthetic analogs exhibit conditional prooxidant properties, it can be referred as multi-faceted compounds (35, 36).  Although the vast majority of studies proved the antioxidant capacity of MLT and its derivatives, some in vitro studies found that MLT promoted the generation of ROS at pharmacological concentrations (μM to mM range); thus, MLT may function as a conditional pro-oxidant.

     MLT levels decline gradually over the lifespan and this may reduce sleep efficacy, accelerate aging process and disrupt many circadian rhythms. MLT exhibits immunomodulatory properties, and a remodeling of immune system function is an integral part of aging. Finally, because MLT is a potent free radical scavenger, its deficiency may result in reduced antioxidant protection in the aging (37). 

 

3. MELATONIN AND OXIDATIVE STRESS

     Evidence shows that neurodegenerative disorders are associated with excessive levels of OS biomarkers and reduced levels of antioxidant defense in the brain (38, 39). OS damage DNA, lipids and proteins as a result of an imbalance between oxidants and antioxidants (40, 41). Protein oxidation triggers inflammatory signal pathways to induce tissue inflammation (42) and resultant diseases including cancer, rheumatoid arthritis, cardiovascular, neurodegenerative and autoimmune diseases (43). Use of molecules with antioxidant activity such as MLT might protect against these OS-related pathologies (44-47). Moreover, under OS situations, many genes of endogenous antioxidant will be up regulated by  MLT (49).

     MLT shows indirect antioxidant activity by inducing antioxidant enzymes (SOD, GSH-Px, CAT and etc.) (50-52), stimulating glutathione synthesis (53), and increasing the efficiency of other antioxidants with synergistic effects (54). Therefore, understanding the antioxidant potential of MLT via different mechanisms is very valuable in order to use of this molecule to protect the organism against OS. The effects of MLT protecting against OS-associated disorders has been well documented (55, 56). Furthermore, several of its favorable activities on human health are often recognized (57, 58).  Brain is exclusively vulnerable to OS. Evidence has shown the favorable effects of MLT to restrict ischemia-reperfusion damages in the central nervous system (59, 60). MLT also able to defend other organs from OS-associated disorders including heart, kidneys, lungs, stomach, skin, and liver (61-63).

     MLT and its metabolites together serve as the effective and competent defense line to defense against OS via an extensive diversity of mechanisms including electron transfer, hydrogen transfer, metal chelation, and mending pharmacological targets. Nevertheless, what appears to be exclusive to the MLT is its unique activities.  MLT and its metabolites are metabolically linked, most of them exist in organisms (64). Thus, the defense of MLT against OS is obviously due to the cascade antioxidant reaction of melatonin with its metabolites. MLT and its metabolites are quite extraordinary in this respect, presenting multipurpose and unique antioxidant defense against OS.

 

4. MELATONIN IN NEUROINFLAMMATION: AGING AND NEURODEGENERATIVE DISEASES

     Neuroinflammation is the result of the excess immune response in central nervous system that causes to death of neurons and damage of brain tissue. Microglias in brain tissue phagocytose the damaged cells and release pro-inflammatory cytokines. In this process, ROS can be formed as the byproducts. In aging and neurodegenerative diseases, dysfunction of microglias and excess of ROS formation cause more neuronal damage and increase in pro-inflammatory cytokines which lead to exaggerated neuroinflammation and neuronal tissue impairment (65). During aging and in neurodegenerative disorders, functions of brain decrease, dementia and cognitive disorders appear. OS is considered to be responsible for age-associated neurodegenerative diseases (66). During cellular respiration, oxygen is delivered to the cells and it is reduced to water through the complexes exist in the electron transport chain (ETC) in mitochondria. In the processes of aging and neurodegenerative diseases the ETC in the neuronal cells is inhibited with excessive amounts of ROS formation which damage mitochondria (67). Free radical mediated mitochondrial dysfunction and neuroinflammation are the pathologic features of aging and neurodegeneration. When ROS trigger oxidative damage in neurons, mitochondrial DNA is injured with the decreased mitochondrial membrane potential, therefore, the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) pathway and caspase-1 are activated. As a result, a large quantity of pro-inflammatory cytokines are released to disturb the functions of normal neurons, finally lead to neuronal cell death (68). In addition, aging and neurodegenerative diseases are also accompanied with diminished MTL production. This makes neurons be more vulnerable to further aggregate the age-related neurodegenerative diseases including Alzhimer’s Disease (AD), Parkinson’s disease (PD) and multiple sclerosis (MS) (69, 70). MLT was reported to be a neuroprotective molecule via its direct/indirect antioxidant activities to maintain mitochondrial homeostasis in aging and neurodegenerative disorders (35, 71, 72). In an in vivo study, the long-term administration of MLT in aged animals significantly decreased OS and improved mitochondrial function and ATP production (73, 74) indicating  that MLT deficiency increases neurodegeneration and aging due to  the elevated oxidative damage in brains in arylalkylamine N-acetyltranferase (AANAT) knocked out mice. On other hand,  MLT administration blocked the cGAS pathway, caspase-1 activation and decreased pro-inflammatory cytokines secretion in these mice. In another study, MLT administration to rats which received neurotoxin and microglia activating amyloid-β significantly decreased their pro-inflammatory cytokine levels (75). These findings indicate that MLT is a potent candidate to prevent the nervous system damage against the free radical attacks and improve mitochondrial function via its antioxidant effect. Thus, melatonin can effectively ameliorate aging associated neurodegenerative diseases.

     In addition to neurodegenerative diseases the antioxidant capacity of melatonin on OS related skin diseases has drawn a great attention of scientists. MLT and its metabolites store in the epidermis, representing the local MLT production and metabolism. Powerful defensive activity of MLT and its metabolites against solar UV skin injury are largely facilitated via its direct radical scavenging and upregulation of the gene expression of antioxidative enzymes (76, 77).  These activities of MLT and its metabolites may majorly occur at the mitochondrial level (78, 79). Evidence supports an association between declines in mitochondrial activity the aging process (80). It was observed that chronic UVR exposure is connected to photo aging and photo-cancer of skin due to the photo-induced overproduction of ROS, which attack the nuclear and mitochondrial DNA (81). MLT and its metabolites in the skin involve in photoprotection, anticancer, wound healing, inhibition of pigmentation, regulation of hair growth, anti-inflammatory action on dermatoses and regulation of skin temperature (82) as well as the regulation of skin functions (83,  84). To analyze the relationship between mitochondrial activity and melanin in melanoma cell lines, Bilska et al. (85) observed a certain influence of MLT, AFMK, 6(OH)MLT, 5-MLT and serotonin on mitochondrial activity. Melatonin with its metabolites considerably reduced melanin content in epidermal melanocytes (86).

     MLT exhibits anti-apoptotic (87) and anti-inflammatory (88) activities which may be mediated by either MLT membrane receptors or nuclear receptors (89, 90). MLT also displays the anti-proliferative activities in cell lines of MNT-1, Sk-Mel-1, Sk-Mel-23 or Sk-Mel-28 (91, 92). Considering the good safety record of MLT and its metabolites, it is a suitable approach to use these molecules for treatments of melanoma alone or in combination with anticancer drugs to increase the efficiency of the therapy (85, 91). MLT, its metabolites and its receptors are present in skin referred as skin melatoninergic system (93). It is known that UVR reduced ATP synthesis from mitochondria (94), while MLT revised UVR-induced inhibition of ATP synthesis in skin. MLT’s capacity of defending oxidative damage and UVR-induced disturbances of ATP synthesis in epidermal keratinocytes was studied by Kleszczyński et al. (95). They observed that MLT had powerful antioxidative properties in UVR-induced oxidative stress in epidermal keratinocytes. Furthermore, MLT upregulates the expression of the antioxidative enzymes including γ-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), and quinone dehydrogenase-1 (NQO1) via the Nrf2-ARE pathway.

     A recent review by Reiter et al (96) discussed the potential mechanisms of melatonin on solid tumor inhibition, i.e., melatonin converts the tumor’s cytosolic aerobic glycolysis known as “Warburg effect” to mitochondrial oxidative metabolism. Mitochondrial oxidative phosphorylation is reliant on the nighttime increased of circulating MLT production (97) and the reduced level of nighttime MLT promote the tumor development. The authors suggested (96) that this main circadian alteration in tumor cells which show aerobic glycolysis could be related to the disrupted circadian MLT rhythm.  MLT directly or indirectly downregulates the expression of pyruvate dehydrogenase kinase (PDK) that plays a role on converting pyruvate to acetyl CoA in the mitochondria (98). If this is hold, it can explain the protective effects of melatonin on many disorders (99). MLT inhibits proliferation the metastatic activity and prompts apoptosis in cancer cells. The capacity of MLT to switch the cytosol glucose metabolism to the mitochondrial metabolism reduces resistance of tumor to conventional chemotherapeutics (100). MLT, as a mitochondria-targeted agent, able to suppresses PDK and motivates PDC (101) to reduce the Warburg effect. As a result, when MLT levels are low during the daytime, cancer cells, particularly the breast cancers are favorite of cytosolic aerobic glycolysis due to the less pyruvate to convert to acetyl CoA. The synthesis of MLT by mitochondria is dependable to the intact ETC (102), higher mitochondrial ATP production is usually associated to reduced ROS (103). MLT promptly stores in mitochondria after administration to promote mitochondrial progressions (104). Another interesting finding is that the insufficiency in SIRT3 in the mitochondria causes malignancy (105). MLT under normal conditions upregulates SIRT3 action (106).

     Serotonin, a precursor of MLT, also exhibits a variety of biological activities in mammalians mostly via G protein coupled receptors or ligand-gated ion channels (5HTR1–7R) (107). Solominski et al. (108), described a serotonin-NAS system in mammalian skin to play a role in neuroendocrine structure by modifying skin homeostasis. Serotonin and NAS are endogenously produced in the epidermal, dermal and adnexal sections of mammalian skin. NAS in serum and tissue is accessible as a substrate for synthesis of MLT in organs having HIOMT.  In skin, the local NAT1/2 converts the serotonin to NAS.  Then, NAS defend   skill cells against the UVB injury.

     Interestingly, MLT can effectively treat SARS-CoV-2 infection (109). The main mechanisms are that melatonin switches glucose glycolysis to oxidative metabolism and upregulates es f hypoxia-inducible factor-1α(HIF-1α) and NF-ҝB pathway (110) to suppress COVID-19 septicemia (111, 112). There is a connection between the secreted phospholipase-A2 and the severity of COVID-19 illness. Reduction of sPLA2-IIA concentration might be a significant approach to prevent multiple organ failure and death due the SARS-CoV-2 infections (113). Activated sPLA2-IIA promotes inflammatory reaction and leads to tissues damage since it hydrolyzes fatty acids (114). By stopping cyclooxygenase activity, MLT reduces the severe inflammatory reaction induced by SARS-CoV-2 infection (115).

     It is well documented that MLT and its metabolites or analogue compounds being able to act as free-radical scavengers and effective antioxidants. Studies also showed the significant roles of MLT and its derivatives in numerous physiological processes and therapeutic utilities including the regulation of circadian rhythm and immune functions. All evidence indicates that MLT is an valuable molecule in the prevention and/or treatment of wide spectrum of disorders (116).

 

5. MELATONIN, MITOPHAGY AND AGING

    Mitophagy is a primary regulatory mechanism for mitochondrial redox integrity and buffers the ROS overproduction. Upon oxidative injury, mitophagy limits the accumulation of dysfunctional mitochondria and alleviates the detrimental effects of redox state failure. A wide spectrum of diseases have been implicated to associated with dysregulation of mitophagy (117). Moderate levels of ROS specifically induce mitophagy to optimize the activity of ROS signaling cascades (118). MLT-mediated mitophagy has shown the promising potency to ameliorate mitochondrial dysfunctions (119). Reduced mitophagy is closely related to decreased longevity since dysfunctional mitochondria are considered as both the source and the target of ROS (120, 121). Impairments in mitophagy may result in diabetes, neurogenerative disorders, cardiovascular pathologies, and cancer.

     Mitochondria is considered as a major pool of MLT due to the reasons that melatonin is synthesized in them and it also can be imported from cytosol via the oligopeptide transporters PEPT1/2. Intramitochondrial MLT effectively scavenges ROS, via its own electron donation capacity and other defensive strategies including its metabolites; these actions of MLT facilitate the maintenance of the redox homeostasis in the mitochondria (122). Mitophagy links number of a complex redox networks which are impacted by MLT. For example,  MLT reduces mitochondrial electron leak and ROS production, blocks mitochondrial permeability transition pore (MPTP) opening to preserve the mitochondrial membrane potential (Δψ) under unfavorable bioenergetic conditions and also activates the uncoupling proteins (UCPs) to adjust the Δψ in normal condition. Mitoprotective effects of MLT is not only restricted to its redox modulatory ability but also related to its signaling function to upregulate expression of antioxidant enzymes, stress responsive genes and inhibition of Cyt-c release. MLT activates heterotrimeric intermembrane space-located G proteins and inhibits stress-induced cytochrome C release (123).  The major pathways of MLT acts on mitophagy include:

     (i) Ubiquitin-dependent PINK1 (PTEN-induced kinase 1)/Parkin-related mitophagy. Upon the occurrence of mitochondrial dysfunction, the outer mitochondrial membrane-located protein PINK1 is responsible for Parkin-mediated ubiquitination of mitochondrial proteins. Autophagy receptors like NDP52, OPTN, and p62 involve ubiquitin-mediated degradation of mitochondria. The members of autophagy core complexes such as VPS34 and ULK1 initiate the formation of autophagosomal membrane which is originated from endoplasmic reticulum.

MLT can induce PINK1 expression via the MT2/Akt/NF-κB pathway, which has a protective role against neuronal injury (124). MLT pretreatment increases both the expression of PINK1 and Parkin in cardiomyocytes. MLT-induced mitophagy reduces the number of dysfunctional mitochondria, restores organelle morphology as well as mitochondrial bioenergetic and redox homeostasis (125). Disturbance of mitophagy to remove the dysfunctional mitochondria often results in cardiomyopathy. MLT enhances mitophagy, alleviates the accumulation of dysfunctional mitochondria and improves cardiac function (30). Dry eye disease is a common eye disorder in elderly population (126). It has been recently reported that MLT-loaded micelles inhibit ROS overproduction and apoptosis in human corneal epithelial cells and ameliorates hyperosmolarity-induced ocular surface damage via PINK1-mediated mitophagy. This intervention may represent an effective treatment for dry eye disease possibly through acting MLT-type 1 receptor (127). Mitochondrial dysfunction is an important underlying factor in neurogenerative diseases such as AD. It was recently reported that long-term oral MLT administration improves memory deficits with reduced amyloid accumulation, downregulation of the number of mitophagy vesicles, diminished expression of PINK1 and Parkin in transgenic mice. Various studies have reported mitochondrial dysfunction in PD animal models with gene knockout or knockdown procedures.  The expression of mitochondrial-related genes, including parkin, and PINK1 were found to be inhibited in these studies. Mutations in Parkin and PINK1 genes are responsible for the development of dysfunctional mitochondrial phenotype and lead to the development of early-onset PD. Mutations in the E3 ubiquitin ligase Parkin and the protein kinase PINK1 are closely related to the development of autosomal-recessive juvenile Parkinsonism. All these mutations are considered as reasons of defective mitophagy (128).  It was shown that MLT restored the expression of PINK1 and Parkin in Parkinsonian Zebrafish embryos (129).

     (ii) Ubiquitin-independent receptor-mediated mitophagy. This pathway needs the recruitment of soluble autophagy receptors such as NIX, BNIP3, and FUNDC1 to the mitochondrial membrane. The receptor proteins recruit LC3, which enables the engulfment of mitochondria by autophagosomes (121).

     (iii) Alternative degradation pathways. Piecemeal mitophagy and mitochondrial-derived vesicle degradation are cellular pathways that mediate localized degradation of mitochondria (130).

     There are several pathologies, syndromes, and physiological processes in which autophagy is involved. Further efforts are required to clarify the possible mitophagy-related role of MLT on the last two pathways.

 

6. MELATONIN DERIVATIVES AS ANTIOXIDANT IN AGING AND NEURODEGENERATIVE DISEASES

     It is widely accepted that ageing is the main risk factor for many neurodegenerative disorders, such as AD, PD, Huntington Disease (HD). Currently no effective drugs are available for the treatment of ageing-associated neurodegenerative diseases. In general, postmitotic cells, such as the brain, are particularly predispose to the ageing associated degeneration. Hallmarks of ageing are genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, stem cell exhaustion and altered intercellular communication associated with exposure to neurodegenerative disorders (131, 132).  MLT is a molecule with capacity to target all these aging hallmarks. Importantly, its derivatives seem to share the similar capacities with melatonin. This makes possible to discover the novel molecules derived from melatonin to function as antioxidant, neuroprotector and aging retarder. There are many properties of MLT as a molecule outstanding.  These include MLT’s very low toxicity (133), its ability to cross blood brain barrier with ease, partially soluble in water and highly soluble in non-polar aprotic solvents such as lipids (134), its metabolites which are capable of offering protection against OS. Therefore, MLT is an outstanding motif for minor alterations to developed novel molecules possibly with broader benefits (135).

      For example, a new MLT derivative (MLTBS) (Figure 1) showed the same pharmacological effects as MLT. Compared with MLT, MLTBS has a benefit of decent water solubility, minor toxicity, and better safety observed in the in vitro and in vivo conditions (136).  

Figure 1.jpg

Fig. 1. Chemical formula of (a) melatonin, (b) sodium 4-(3-(2-acetamidoethyl)-5-methoxy-1H-indol-1-yl) butane-1-sulfonate (MLTBS).

 

     MLT and some related natural molecules also show antioxidant properties. Among these molecules the most significant ones are MLT’s metabolites N1-acetyl-5-methoxykynuramine (AMK), N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), cyclic 3-hydroxymelatonin (C3OHM), 5-methoxytryptamine (5MTA), and 6-hydroxymelatonin (6OHM) (Figure 2). C3OHM is a product of the MLT interaction with hydroxyl radical (96). AFMK is produced after C3OHM interacts with other free radicals. Then AMK is formed from the reaction between the radicals and AFMK (137). AFMK has inhibitory effect on lipid peroxidation and OS-induced neuronal damage (138). 6OHM is an inhibitor of quinolinic-acid induced neurotoxicity (139).

Figure 2.jpg

Fig. 2. Chemical formula of (a) N1 -acetyl-5-methoxykynuramine (AMK), (b) N1 -acetyl-N2 -formyl-5-methoxykynuramine (AFMK) and (c) cyclic 3-hydroxymelatonin (c3OHM).

     N-acetylserotonin (NAS) is an intermediate molecule that is formed from serotonin and has neuroprotective effect in neurological disorders (140). It was found that NAS has strong antioxidant properties (141). NAS is present in some parts of the brain (142). Naturally produced MLT derivatives and some precursors such as serotonin (5HT) (143), 5-hydroxytryptophan (5HTP) and 5-methoxytryptamine (5MTA) (Figure 3) are versatile antioxidants. The serotonin system in human is very significant, particularly in neuronal conduction and neuromodulation. 5-HT shows strong antioxidant properties and reacts with a greater attraction to unsaturated lipids and able to interrupt the diffusion of free radicals (143).

     There are indications associated the theory that chemical alterations to MLT’s structure leads to the development of new molecules with an extensive variety of anticipated activities. Besides, these compounds might have superior therapeutic benefits than MLT.

Figure 3.jpg

Fig. 3. Chemical formula of (a) N-acetylserotonin (NAS), (b) serotonin, (c) 5-hydroxytryptophan (5HTP) and (d) 5-methoxytryptamine (5MTA).

     Systematic rational researches for development of the novel MLT derivatives were performed using different strategies and computer-assisted procedures. Reina et al. (144) was synthesized new derivatives by addition of different simple functional groups such as -OH, -NH2, -SH and -COOH to the MLT molecule. Results revealed that 5 MLT-derivatives have been recognized as scavengers of free radicals, by electron transfer and/or H transfer.

    Antioxidant defense is a multifaceted procedure that includes diverse chemical and non-chemical reactions. There are numerous features on the performance of the developed molecules. Inspired for the interesting properties of MLT, the design and synthesis of MLT-like compounds is a rapidly developing research area (145, 146). The antioxidant properties of some MLT derivatives with a sulfhydryl group have better antioxidant activity than that of MLT (147). Moreover indole-based MLT hydrazine derivatives containing 2-phenylindole (148), indole-3-propionamides (149) and N-methylindole (150) derivatives were potent free radical scavengers observed in the in vitro experiments. Between the hydrazide-MLT derivatives, 5-chloroindole hydrazide were established to be very effective as antioxidant (151). Alterations in modification of the 5-methoxy and 3-acylaminoethyl side chain of MLT have shown the encouraging aspect to make novel molecules with improved antioxidant capacity compared to MLT (152). Indole-based analogues of MLT such as indole amino acid derivatives have been synthesized and analyzed for antioxidant capacity. Their activity to scavenge DPPH (2,2- difenil-1-picrylhydrazyl) was parallel to that of MLT, while their effectiveness as inhibitors of lipid peroxidation was advanced (153). Additional research of other properties of the novel MLT analogues are still desirable from both experimental and theoretical methodologies. But it is likely that further research will assist to discover new molecules concerning antioxidant protection and possibly neuroprotection.

 

7. CONCLUSION REMARKS

     Age-associated neurodegenerative diseases are becoming a serious public health issue. OS and redox homeostasis play essential part in aging and neurodegenerative diseases. Antioxidants such as vitamin E, vitamin C, β carotene, and some flavonoids have limited success as effective prophylaxis or treatment remedy. Assumed the significance of OS in the pathogenesis of numerous diseases and aging, antioxidant should be suitable for treatment of these OS associated disorders. During aging the redox homeostasis is challenged since excessive OS with aging disturbs particularly the regulatory structures of nerve system, endocrine and immune response. MLT is universally presented molecule not only in the pineal gland but also in many organs and tissues (154). It is a potent endogenously produced antioxidant. MLT’s defense against OS exhibits cascade reaction, i.e., not only melatonin but also its metabolites possess antioxidant capacity (36, 155). Circadian rhythms are essential timers establishing the routine and physiology of organisms. They are associated with cellular redox regulation. Metabolism, redox homeostasis, circadian rhythms, and nutrition directly impact aging process.

     MLT as antioxidant has the capacity preserves the redox homeostasis. Its mechanisms are multiple.  Melatonin can directly scavenge free radicals and indirectly upregulation of expression and activities of antioxidant enzymes and downregulation of the prooxidant enzymes (156). Nevertheless, the molecular mechanism underlying the precise act of MLT is not entirely understood. Aging is related with a substantial decrease in endogenous MLT synthesis, an increase of OS and other metabolic alterations (157). MLT is an effective defender of mitochondria due to its lipophilic properties that protects the mitochondrial inner membrane against OS (136). It also conserves mitochondrial activities by prompting mitofusin-2 activity, the main controller of mitochondrial cellular metabolism (158). MLT preserves calcium homeostasis in cardiomyocytes by preventing OS-linked disorder of sarco/endoplasmic reticulum calcium ATPase (SERCA) and sodium-calcium exchanger (NCX) proteins (159). Long-term of MLT treatment benefits glucose homeostasis and reduces insulin resistance in animal studies. Antioxidant activity of MLT is adequate to improve insulin resistance via destruction of   Jun kinases/stress-activated protein kinases (JNK) stimulation and phosphoenolpyruvate carboxykinase (PEPCK) expression due to decreased OS, producing better glucose homeostasis and reestablished hepatic insulin signaling (160). MLT signaling is a key regulator of glucose homeostasis and energy metabolism (161). Obesity as a syndrome of disturbed lipid homeostasis is also the target of melatonin. MLT exhibits favorable properties in refining lipid metabolism and circadian rhythm homeostasis (162). MLT regulates iron homeostasis via prompting hepcidin expression in hepatocytes (163). It also has defensive roles on the activity of the exocrine pancreas, Ca2+ signaling and the mitochondrial integrity (164). Since MLT is synthesized in mitochondria, a close connection is expected between MLT and mitochondria (Figure 4) including  scavenging mitochondrial originated ROS, promoting  uncoupling proteins (UCP) activity, reducing the mitochondrial permeability transition pore (mtPTP) opening, preventing mitochondrial dysfunction from oxidative damage by preserving cardiolipin integrity, improving calcium handling, inhibiting mtDNA release and activation of cytosolic DNA-mediated inflammatory response in neurons (165-171). All these were illustrated in the Figure 4. The research on MLT activity in cellular homeostasis has produced inspiring information, which have led to investigators to share their knowledge concerning the beneficial effects of MLT in human health. Generally, MLT plays a vital role in the regulation of metabolism and redox homeostasis. Nevertheless, there remains necessity for additional convincing clinical research to clarify certain actions which MLT and its metabolites as well as the related receptors are responsible to the regulation of diverse metabolic procedures in organisms. Given that there are numerous activities of MLT, upcoming clinical studies employing MLT should be encouraged to use in the management of many diseases associated with OS.

Figure 4-1.jpg

Fig. 4.  Summary of the potential effects of melatonin on mitochondria.

   

ACKNOWLEDGEMENTS

     The authors have no relevant financial or non-financial support to disclose.

 

AUTHORSHIP

     SS and HS have been involved in writing the “Introduction”, “Melatonin derivatives as antioxidant in aging and neurodegenerative diseases” and “Conclusion remarks” parts.  UC and MCA have made substantial contributions to “Cellular redox homeostasis, reactive oxygen species” and “Melatonin, Autophagy and aging” parts. HGO and BE have been involved “Melatonin and Oxidative Stress” and “Melatonin in Neuroinflammation: aging and neurodegenerative diseases” parts.

 

CONFLICT OF INTERESTS

     Authors declare no conflict of interest

 

REFERENCES

 

  1. Le Gal K, Schmidt EE, Sayin VI (2021) Cellular redox homeostasis. Antioxidants (Basel). 10 (9): 1377.

  2. Yanar K, Simsek B, Çakatay U (2019) Integration of oxidative related redox homeostasis, aging, and circadian rhythm. Rejuvenation Res. 22 (5): 409-419.

  3. Jiang J, et al. (2021) Melatonin ameliorates PM2.5 -induced cardiac perivascular fibrosis through regulating mitochondrial redox homeostasis. J. Pineal Res. 70 (1): e12686.

  4. Reiter RJ, Tan DX, Fuentes-Broto L (2010) Melatonin: a multitasking molecule. Prog. Brain Res. 181: 127-51.

  5. Zisapel N (2018) New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation.  Br. J. Pharmacol. 175 (16): 3190–3199.

  6. Hardeland R (2009) Melatonin signaling mechanisms of a pleiotropic agent. Biofactors 35 (2): 183-192.

  7. Acuna-Castroviejo D, et al. (2002) Melatonin, mitochondrial homeostasis and mitochondrial-related diseases. Curr. Top. Med. Chem.  2: 133-151.

  8. Samanta S (2020) Melatonin: an endogenous miraculous indolamine, fights against cancer progression. J. Cancer Res. Clin. Oncol. 146 (8): 1893-1922.

  9. Hardeland R, Pandi-Perumal SR (2002) Melatonin, a potent agent in antioxidative defense: actions as a natural food constituent, gastrointestinal factor, drug and prodrug. Nutr. Metab. (Lond) 2: 22.

  10. Zhang, H-M, Zhang, Y (2014) Melatonin: a well-documented antioxidant with conditional pro-oxidant actions. J. Pineal Res. 57 (2): 131-146.

  11. Zisapel N (2010) Melatonin and sleep. Open Neuroendocrinol J. 3: 85–95.

  12. Kopustinskiene DM, Bernatoniene J (2021) Molecular mechanisms of melatonin-mediated cell protection and signaling in health and disease. Pharmaceutics 13 (2):129.

  13. Majidinia M, Reiter RJ, Shakouri SK, Yousefi B (2018) The role of melatonin, a multitasking molecule, in retarding the processes of ageing. Ageing Res. Rev. 47: 198–213.

  14. Carrillo-Vico A, Guerrero JM, Lardone PJ, Reiter RJ (2005) A review of the multiple actions of melatonin on the immune system. Endocrine 27 (2): 189–200.

  15. Carrillo-Vico A, Lardone PJ, Alvarez-Sanchez N, Rodriguez-Rodriguez, Guerrero J.M (2013) Melatonin: Buffering the immune system. Int. J. Mol. Sci. 14 (4): 8638–8683.

  16. Acuna-Castroviejo D, et al. (2017) Melatonin, clock genes and mitochondria in sepsis. Cell. Mol. Life Sci. 74 (21): 3965–3987.

  17. Won E, Na KS, Kim YK (2021) Associations between melatonin, neuroinflammation, and brain alterations in depression. Int. J. Mol. Sci. 23 (1): 305.

  18. De la Fuente M, Miquel J (2009) An update of the oxidation-inflammation theory of aging: the involvement of the immune system in oxi-inflamm-aging. Curr. Pharm. Des. 15 (26): 3003–3026.

  19. Hardeland R (2019) Aging, melatonin and the pro- and anti-inflammatory networks. Int. J. Mol. Sci. 20 (5):1223.

  20. Gimenez VMM, et al.  (2022) Melatonin as an anti-aging therapy for age-related cardiovascular and neurodegenerative diseases. Front Aging Neurosci. 14: 888292. doi: 10.3389/fnagi.2022.888292.

  21. Farooq MA, et al. (2019) Acquiring control: The evolution of ROS-induced oxidative stress and redox signaling pathways in plant stress responses. Plant Physiol. Biochem. 141: 353-369.

  22. Yang ZH, Wang J, Chan KS (2011) Spin accumulation in triplet Josephson junction. J Phys Condens Matter. 23 (8): 085701. doi: 10.1088/0953-8984/23/8/085701.

  23. Gerschman R, Gilbert DL, Nye SW, Dwyer P, Fenn WO (1954) Oxygen poisoning and x-irradiation: a mechanism in common. Science 119 (3097): 623–626.

  24. Watabe N, Ishida Y, Ochiai A, Tokuoka Y, Kawashima N (2007) Oxidation decomposition of unsaturated fatty acids by singlet oxygen in phospholipid bilayer membranes. J. Oleo Sci. 56 (2): 73–80.

  25. Schieber M, Chandel NS (2014) ROS function in redox signaling and oxidative stress. Curr. Biol. 24 (10): R453-462.

  26. Tan DX, et al. (2000) Significance of melatonin in antioxidative defense system: reactions and products. Biol. Signals Recept. 9 (3-4):137–159.

  27. Cardoso S, Moreira PI (2022) Targeting mitochondria and redox dyshomeostasis in brain ageing: an update. In: Çakatay, U. (eds) Redox Signaling and Biomarkers in Ageing. Healthy Ageing and Longevity, vol 15. Springer, Cham. https://doi.org/10.1007/978-3-030-84965-8_8

  28.  Ursini F, Maiorino M, Forman HJ (2016) Redox homeostasis: The golden mean of healthy living. Redox Biol. 8: 205-215.

  29. Ludovico P, Burhans WC (2014) Reactive oxygen species, ageing and the hormesis police. FEMS Yeast Res. 14 (1): 33-39.

  30. Wang J, et al. (2019) Antioxidant and pro-oxidant activities of melatonin in the presence of copper and polyphenols in vitro and in vivo. Cells 8: 903.

  31. He L, He T, Farrar S, Ji L, Liu T, Ma X (2017) Antioxidants maintain cellular redox homeostasis by elimination of reactive oxygen species. Cell Physiol. Biochem. 44(2):532-553. doi: 10.1159/000485089.

  32. Okeke ES, Ogugofor MO, Nkwoemeka NE, Nweze EJ, Okoye CO (2022) Phytomelatonin: a potential phytotherapeutic intervention on COVID-19-exposed individuals. Microbes Infect. 24 (1): 104886.

  33. Kuciel-Lewandowska J, et al. (2020) The impact of health resort treatment on the nonenzymatic endogenous antioxidant system. Oxid. Med. Cell Longev. 2020: 8423105.

  34. Mannino G, Pernici C, Serio G, Gentile C, Bertea CM (2021) Melatonin and phytomelatonin: chemistry, biosynthesis, metabolism, distribution and bioactivity in plants and animals-an overview. Int. J. Mol. Sci. 22 (18): 9996.

  35. Zhang H-M, Zhang Y (2014) Melatonin: a well-documented antioxidant with conditional pro-oxidant actions. J. Pineal Res. 57 (2):131–146.

  36. Gurer-Orhan H, Suzen S (2015) Melatonin, its metabolites and its synthetic analogs as multi-faceted compounds: Antioxidant, prooxidant and inhibitor of bioactivation reactions. Curr. Med. Chem. 22 (4):490-499.

  37. Karasek M (2004) Melatonin, human aging, and age-related diseases. Exp. Gerontol. 39 (11-12):1723–1729.

  38. Finaud, J, Lac G, Filaire E (2012) Oxidative stress. Sports Medicine 36 (4): 327–358.

  39. Suzen, S, Tucci P, Profumo E, Buttari B, Saso L (2022) A pivotal role of Nrf2 in neurodegenerative disorders: A new way for therapeutic strategies. Pharmaceuticals 15 (6): 692.

  40. Sies H, Berndt C, Jones DP (2017) Oxidative stress. Annu. Rev. Biochem. 86: 715–748.

  41. Sies, H, Jones D (2007) Editor-in-Chief: George Fink, Hardcover ISBN: 9780120885039, eBook ISBN: 9780080547961, Encyclopaedia of stress. 45–48

  42. Ghezzi P (2014) Linkage of inflammation and oxidative stress via release of glutathionylated peroxiredoxin-2, which acts as a danger signal. Proc. Natl. Acad. Sci. 111 (33): 12157–12162.

  43. Droge W (2002) Free radicals in the physiological control of cell function. Physiol. Rev. 82 (1): 47–95.

  44. Birben E, Sahiner UM, Sackesen C, Erzurum S, Kalayci O (2012) Oxidative stress and antioxidant defense. World Allergy Organ. J. 5 (1): 9–19.

  45. Matuszak Z, Reszka KJ, Chignell CF (1997) Reaction of melatonin and related indoles with hydroxyl radicals: EPR and spin trapping investigations. Free Radic. Biol. Med. 23 (3): 367–372.

  46. Purushothaman A, Sheeja AA, Janardanan D (2020) Hydroxyl radical scavenging activity of melatonin and its related indolamines. Free Radic. Res. 54 (5): 373–383.

  47. Reiter RJ, et al. (2003) Melatonin as an antioxidant: Biochemical mechanisms and pathophysiological implications in humans. Acta Biochim. Pol. 50 (4): 1129–1146.

  48. Reiter RJ, Tan DX, Osuna C, Gitto E (2000) Actions of melatonin in the reduction of oxidative stress. A review. J. Biomed. Sci. 7 (6):444-458.

  49. Vázquez J, et al. (2017) Melatonin reduces oxidative stress damage induced by hydrogen peroxide in saccharomyces cerevisiae. Front. Microbiol. 8:1066.

  50. Liu F, Ng TB (2000) Effect of pineal indoles on activities of the antioxidant defense enzymes superoxide dismutase, catalase, and glutathione reductase, and levels of reduced and oxidized glutathione in rat tissues. Biochem. Cell Biol. 78 (4): 447–453.

  51. Öztürk G, Coşkun S, Erbaş D, Hasanoǧlu E (2000) The effect of melatonin on liver superoxide dismutase activity, serum nitrate and thyroid hormone levels. Jap. J. Physiol. 50 (1): 149–153.

  52. Tan DX, et al. (2005) Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger. Curr. Top. Med. Chem.  2 (2): 181–197.

  53.  Limón-Pacheco JH, Gonsebatt ME (2010) The glutathione system and its regulation by neurohormone melatonin in the central nervous system. Cent. Nerv. Syst. Agents Med. Chem. 10 (4): 287-297.

  54. Montilla P, et al. (2001) Melatonin versus vitamin E as protective treatment against oxidative stress after extra-hepatic bile duct ligation in rats. J. Pineal Res. 31 (2): 138–144.

  55. Galano A, Tan DX, Reiter RJ (2011) Melatonin as a natural ally against oxidative stress: a physicochemical examination. J. Pineal Res. 51 (1):1-16.

  56. Borges LDS, et al. (2015) Melatonin decreases muscular oxidative stress and inflammation induced by strenuous exercise and stimulates growth factor synthesis. J. Pineal Res. 58 (2):166-172.

  57. Gitto E, Aversa S, Reiter RJ, Barberi I, Pellegrino S (2011) Update on the use of melatonin in pediatrics. J. Pineal Res. 50 (1): 21-28.

  58. Sanchez-Barcelo EJ, Mediavilla MD, Tan DX, Reiter RJ (2010) Clinical uses of melatonin: evaluation of human trials. Curr. Med. Chem. 17 (19): 2070-2095.

  59. Bhattacharya P, Pandey AK, Paul S, Patnaik R (2014) Melatonin renders neuroprotection by protein kinase C mediated aquaporin-4 inhibition in animal model of focal cerebral ischemia. Life Sci. 100 (2): 97-109.

  60. Paterniti I, Cordaro M, Esposito E, Cuzzocrea S (2016) The antioxidative property of melatonin against brain ischemia. Expert Rev. Neurother. 16 (7): 841-848.

  61. Simko F, et al. (2014) Melatonin reduces cardiac remodeling and improves survival in rats with isoproterenol-induced heart failure. J. Pineal Res. 57 (2):177-184.

  62. Jaworek J, Brzozowski T, Konturek SJ (2005) Melatonin as an organoprotector in the stomach and the pancreas. J. Pineal Res. 38 (2):73-83.

  63. Sierra AF, Ramírez MLG, Campmany ACC, Martínez AR, Naveros BC (2013) In vivo and in vitro evaluation of the use of a newly developed melatonin loaded emulsion combined with UV filters as a protective agent against skin irradiation. J. Dermatol. Sci. 69 (3): 202-214.

  64.  Galano A, Reiter RJ (2018) Melatonin and its metabolites vs oxidative stress: From individual actions to collective protection. J. Pineal Res. 65 (1): e12514.

  65. Pizza V, Agresta A, WD’Acunto C, Festa M, Capasso A (2012) Neuroinflamm-aging and neurodegenerative diseases: an overview. CNS Neurol. Disord. Drug Targets. 10 (5): 621–634.

  66. Olanow CW (1993) A radical hypothesis for neurodegeneration. Trends Neurosci. 16 (11): 439–444.

  67. Acuna-Castroviejo D, et. al. (2001) Melatonin, mitochondria, and cellular bioenergetics. J. Pineal Res. 30 (2): 65–74.

  68. Madabhushi R, Pan L, Tsai LH (2014) DNA damage and its links to neurodegeneration. Neuron 83 (2): 266–282.

  69. Kalliolia et al. (2014) Plasma melatonin is reduced in Huntington’s disease. Mov. Disord. 29 (12): 1511–1515.

  70. Liu RY, Zhou JN, Van Heerikhuize J, Hofman MA, Swaab DF (1999) Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer’s Disease, and apolipoprotein E-ε4/4 Genotype. J. Clin. Endocrinol. Metab. 84 (1): 323–327.

  71. He R, et al. (2018) Melatonin resists oxidative stress-induced apoptosis in nucleus pulposus cells. Life Sci. 199: 122–130.

  72. Lopez A, et al. (2009) Melatonin protects the mitochondria from oxidative damage reducing oxygen consumption, membrane potential, and superoxide anion production. J. Pineal Res. 46 (2): 188–198.

  73. Carretero M, et al. (2009) Long-term melatonin administration protects brain mitochondria from aging. J. Pineal Res. 47 (2): 192–200.

  74. Jauhari A, et al. (2020) Melatonin inhibits cytosolic mitochondrial DNA–induced neuroinflammatory signaling in accelerated aging and neurodegeneration. J. Clin. Invest. 130 (6): 3124–3136.

  75. Rosales-Corral S, et al. (2003) Orally administered melatonin reduces oxidative stress and proinflammatory cytokines induced by amyloid-β peptide in rat brain: A comparative, in vivo study versus vitamin C and E. J. Pineal Res. 35 (2): 80–84.

  76. Slominski AT, et al. (2017) Metabolism of melatonin in the skin: Why is it important? Exp. Dermatol. 26 (7): 563-568. 

  77. Slominski AT, et al. (2014) Local melatoninergic system as the protector of skin integrity. Int. J. Mol. Sci. 15: 1770519.

  78. Bocheva G, et al (2022) Protective role of melatonin and its metabolites in skin aging. Int. J. Mol. Sci. 23 (3):1238-1252. 

  79. 7Ferlazzo N, et al. (2020) Is melatonin the cornucopia of the 21st century? Antioxidants (Basel). 9 (11):1088-102.

  80. DeBalsi KL, Hoff KE, Copeland W.C (2017) Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases. Ageing Res. Rev. 33: 89–104.

  81. Birch-Machin MA., Bowman A (2016) Oxidative stress and ageing. Br. J. Dermatol. 175: 26–29.

  82. Slominski AT, et al. (2018) Melatonin: a cutaneous perspective on its production, metabolism, and functions. J. Invest Dermatol. 138 (3): 490-499.

  83. Rusanova I, et al. (2019) Protective effects of melatonin on the skin: future perspectives. Int. J. Mol. Sci. 20 (19): 4948-4962.

  84. Kim TK, et al. (2013) Metabolism of melatonin and biological activity of intermediates of melatoninergic pathway in human skin cells. FASEB J. 27: 2742-2755.

  85. Bilska B, et al. (2021) Mitochondrial function is controlled by melatonin and its metabolites in vitro in human melanoma cells. J. Pineal Res. 70 (3): e12728.

  86. Kim TK, et al. (2015) Melatonin and its metabolites accumulate in the human epidermis in vivo and inhibit proliferation and tyrosinase activity in epidermal melanocytes in vitro. Mol. Cell Endocrinol. 404: 1- 8.

  87. Kleszczyński K, et al. (2018) Melatonin and its metabolites ameliorate UVR-induced mitochondrial oxidative stress in human MNT-1 melanoma cells. Int. J. Mo.l Sci. 19 (12): e3786.

  88. Kleszczyński K, et al. (2015)Melatonin compensates silencing of heat shock protein 70 and suppresses ultraviolet radiation-induced inflammation in human skin ex vivo and cultured keratinocytes. J. Pineal Res. 58 (1):117-126.

  89. Tan DX, Reiter RJ (2019)Mitochondria: the birth place, battle ground and the site of melatonin metabolism in cells. Melatonin Res. 2 (1): 44-66.

  90. Reiter RJ,et al. (2017)Melatonin as a mitochondria-targeted antioxidant: one of evolution's best ideas. Cell Mol. Life Sci. 74 (21): 3863-3881.

  91. Kleszczyński K, et al. (2019) Melatonin exerts oncostatic capacity and decreases melanogenesis in human MNT-1 melanoma cells. J. Pineal Res. 67 (4): e12610.

  92. Cabrera J, et al. (2010) Melatonin decreases cell proliferation and induces melanogenesis in human melanoma SK-MEL-1 cells. J. Pineal Res. 49 (1): 45- 54.

  93. Slominski RM, et al. (2012) Melatonin membrane receptors in peripheral tissues: distribution and functions. Mol. Cell Endocrinol.  351:152– 166.

  94. Bowman A, Birch-Machin MA (2015) Mitochondrial DNA as a biosensor of UV exposure in human skin. Methods Mol. Biol. 1265: 379– 388.

  95. Kleszczyński K, Zillikens D, Fischer TW (2016) Melatonin enhances mitochondrial ATP synthesis, reduces reactive oxygen species formation, and mediates translocation of the nuclear erythroid 2-related factor 2 resulting in activation of phase-2 antioxidant enzymes (γ-GCS, HO-1, NQO1) in ultraviolet radiation-treated normal human epidermal keratinocytes (NHEK). J. Pineal Res. 61 (2):187-197.

  96. Reiter RJ, Sharma R, Ma Q (2021) Switching diseased cells from cytosolic aerobic glycolysis to mitochondrial oxidative phosphorylation: A metabolic rhythm regulated by melatonin? J. Pineal Res. 70 (1): e12677.

  97. Blask DE, et al. (2014) Light exposure at night disrupts host/cancer circadian regulatory dynamics: impact on the Warburg effect, lipid signaling and tumor growth prevention. PLoS One9 (8): e102776.

  98. Reiter RJ, et al. (2019) Inhibition of pyruvate dehydrogenase kinase: a proposed mechanism by which melatonin causes cancer cells to overcome cytosolic glycolysis, reduce tumor biomass and reverse insensitivity to chemotherapy. Melatonin Res. 2: 105- 119.

  99. Zhao D, et al. (2019) Melatonin synthesis and function: evolutionary history in animals and plants. Front Endocrinol. (Lausanne) 10: 249-68. 

  100. Reiter RJ, et al. (2020) Melatonin inhibits Warburg-dependent cancer by redirecting glucose oxidation to the mitochondria: a mechanistic hypothesis. Cell Mol. Life Sci. 77 (13): 2527-2542.

  101. Giudice A, et al. (2018) The effect of light exposure at night (LAN) on carcinogenesis via decreased nocturnal melatonin synthesis. Molecules 23 (6): 1308-1324.

  102. Leon J, et al. (2004) Melatonin and mitochondrial function. Life Sci. 75 (7): 765–790.

  103. Reiter RJ, et al. (2018) Melatonin mitigates mitochondrial meltdown: interactions with SIRT3. In.t J. Mol. Sci. 19: 8-12.

  104. Acuña-Castroviejo D, et al. (2018) Melatonin actions in the heart; more than a hormone. Melatonin Res 1: 21–26.

  105. Kim HS, et al. (2010) SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 17 (1): 41–52.

  106. Han L, et al. (2017) Melatonin protects against maternal obesity-associated oxidative stress and meiotic defects in oocytes via the SIRT3-SOD2-dependent pathway. J. Pineal Res. 63: 3-12.

  107.  Lv J, Liu F (2017) The role of serotonin beyond the central nervous system during embryogenesis. Front. Cell Neurosci. 11:74-88.

  108. Slominski AT, et al. (2020) Characterization of serotonin and N-acetylserotonin systems in the human epidermis and skin cells. J. Pineal Res. 68 (2): e12626. 

  109. Reiter RJ, et al. (2022) Melatonin: highlighting its use as a potential treatment for SARS-CoV-2 infection. Cell Mol. Life Sci. 79 (3): 143.

  110. Tian M, et al. (2021) HIF-1alpha promotes SARS-CoV-2infection and aggravates inflammatory responses to COVID-19. Signal Transduct. Target Ther. 6 (1): 308-318.

  111. Florido J, et al. (2022) Understanding the mechanism of action of melatonin, which induces ROS production in cancer cells. Antioxidants (Basel). 11 (8):1621-1638.

  112.  Reiter RJ, Sharma R, Rosales-Corral S (2021) Anti-warburgeffect of melatonin: a proposed mechanism to explain its inhibition of multiple diseases. Int. J., Mol. Sci. 22 (2): 764-86.

  113. Snider JM, et al. (2021) Group IIA secreted phospholipase A2 isassociated with the pathobiology leading to COVID-19 mortality. J. Clin. Invest. 131 (19): e149236.

  114. Letsiou E, Htwe YM, Dudek SM (2021) Secretory phospholi-pase A2 enzymes in acute lung injury. Cell Biochem. Biophys. 79: 609–617. 

  115. Anderson G, Carbone A, Mazzoccoli G (2020) Aryl hydrocar-bon receptor role in co-ordinating SARS-CoV-2 entry and symptomatology: Linking cytotoxicity changes in COVID-19and cancers; modulation by racial discrimination stress. Biology (Basel). 9 (9): 249-258.

  116. Karaaslan C, Suzen S (2015) Antioxidant properties of melatonin and its potential action in diseases. Curr. Top. Med. Chem. 15 (9): 894-903.

  117. Garza-Lombó C, Pappa A, Panayiotidis MI, Franco R (2020) Redox homeostasis, oxidative stress and mitophagy. Mitochondrion. 51: 105-117.

  118. Frank M, et al. (2012) Mitophagy is triggered by mild oxidative stress in a mitochondrial fission dependent manner. Biochim. Biophys. Acta 1823 (12): 2297-2310.

  119. Atayik MC, Yanar K, Çakatay U (2022) Redox proteostasis in subcellular aging. In: Çakatay U (ed) Redox Signaling and Biomarkers in Ageing. Springer International Publishing Cham. pp 209–228.

  120.  Chen G, Kroemer G, Kepp O (2020) Mitophagy: an emerging role in aging and age-associated diseases. Front. Cell Dev. Biol. 8: 200.

  121.  Lin Q, et al. (2021) New insights into mitophagy and stem cells. Stem Cell Res. Ther. 12 (1): 452.

  122. Atayik MC, Çakatay U. (2022) Mitochondria-targeted senotherapeutic interventions. Biogerontology. 23 (4):401-423.

  123. Suofu Y, et al. (2017) Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release. Proc. Natl. Acad. Sci. U .S .A. 114 (38): E7997–E8006.

  124.  Onphachanh X, et al. (2017) Enhancement of high glucose-induced PINK1 expression by melatonin stimulates neuronal cell survival: Involvement of MT(2) /Akt/NF-κB pathway. J. Pineal Res. 63 (2): e12427.

  125.  Atayik MC, Çakatay U. (2022) Melatonin-related signaling pathways and their regulatory effects in aging organisms. Biogerontology. 23 (5): 529-539. doi: 10.1007/s10522-022-09981-y.

  126. Ding J, Sullivan D (2012) Aging and dry eye disease. Exp. Gerontol. 47 (7): 483-490.  

  127. Xu J, et al. (2022) Copolymer micelle-administered melatonin ameliorates hyperosmolarity-induced ocular surface damage through regulating PINK1-mediated mitophagy. Curr. Eye Res. 47 (5): 688-703.

  128. Luo F, et al. (2020) Melatonin and autophagy in aging-related neurodegenerative diseases. Int. J. Mol. Sci. 21 (19): 7174.

  129. Díaz-Casado ME, et al. (2016) Melatonin rescues zebrafish embryos from the parkinsonian phenotype restoring the parkin/PINK1/DJ-1/MUL1 network. J. Pineal Res. 61 (1): 96–107.

  130. Bakula D, Scheibye-Knudsen M (2020) MitophAging: Mitophagy in aging and disease. Front. Cell Dev. Biol. 8: 239.

  131. Hou Y, et al. (2019) Ageing as a risk factor for neurodegenerative disease. Nat. Rev. Neurol. 15 (10): 565–581.

  132. Bubenik GA, Konturek SJ (2011) Melatonin and aging: prospects for human treatment. J. Physiol. Pharmacol. 62 (1):13-19.

  133. Zhang J, et al. (2020) Synthesis of a new water-soluble melatonin derivative with low toxicity and a strong effect on sleep aid. ACS Omega 5 (12):6494-6499.

  134. Alluri H, et al. (2016) Melatonin preserves blood-brain barrier integrity and permeability via matrix metalloproteinase-9 inhibition. PLoS One 11 (5): e0154427.

  135. Galano A, Guzmán-López EG, Reiter RJ (2021) Potentiating the benefits of melatonin through chemical functionalization: possible impact on multifactorial neurodegenerative disorders. Int. J. Mol Sci. 22 (21):11584.

  136. Tan DX, Hardeland R, Manchester LC, Galano A, Reiter RJ (2014) Cyclic-3-hydroxymelatonin (C3HOM), a potent antioxidant, scavenges free radicals and suppresses oxidative reactions. Curr. Med. Chem. 21 (13): 1557–1565.

  137.  Reiter RJ, Tan,DX, Galano A (2014) Melatonin reduces lipid peroxidation and membrane viscosity. Front. Physiol. 5: 377.

  138. Burkhardt S, et al. (2002) DNA oxidatively damaged by chromium(III) and H2O2 is protected by the antioxidants melatonin, N1-acetyl-N2-formyl-5-methoxykynuramine, resveratrol and uric acid. Int. J. Biochem. Cell Biol. 33 (8): 775–783.

  139. Maharaj DS, et al. (2005) 6-Hydroxymelatonin protects against quinolinic-acid-induced oxidative neurotoxicity in the rat hippocampus. J. Pharm. Pharmacol. 57 (7): 877–881.

  140. Zhou H, et al. (2014) N-acetyl-serotonin offers neuroprotection through inhibiting mitochondrial death pathways and autophagic activation in experimental models of ischemic injury. J. Neurosci. 34 (8): 2967-2978.

  141. Oxenkrug G, Requintina P, Bachurin S (2001) Antioxidant and antiaging activity of N-acetylserotonin and melatonin in the in vivo models. Ann. N. Y. Acad. Sci. 939: 190–199.

  142. Jang SW, et al. (2010) N-acetylserotonin activates TrkB receptor in a circadian rhythm. Proc. Natl. Acad. Sci. U. S. A. 107 (8): 3876–3881.

  143. Azouzi S, et al. (2017) Antioxidant and membrane binding properties of serotonin protect lipids from oxidation. Biophys. J. 112 (9): 1863-1873.

  144. Reina M, et al. (2018) A computer-assisted systematic search for melatonin derivatives with high potential as antioxidants. Melatonin Res. 1 (1): 27-58.

  145. Suzen S (2013) Melatonin and synthetic analogs as antioxidants. Curr. Drug Del. 10 (1): 71-75. 

  146.  Galano A (2016) Computational-aided design of melatonin analogues with outstanding multifunctional antioxidant capacity. RSC Advances 6 (27): 22951-22963.

  147. Ng TB, Liu F, Zhao L (2000) Antioxidative and free radical scavenging activities of pineal indoles. J. Neural. Transm. 107 (11): 1243–1251.

  148. Suzen S, Bozkaya P, Coban T, Nebioglu D (2006) Investigation of the in vitro antioxidant behaviour of some 2-phenylindole derivatives: Discussion on possible antioxidant mechanisms and comparison with melatonin. J. Enzym. Inhib. Med. Chem.  21 (4): 405–411.

  149. Ates-Alagöz Z, Coban T, Suzen S (2005) A comparative study: Evaluation of antioxidant activity of melatonin and some indole derivatives. Med. Chem. Res. 14: 169–179.

  150. Shirinzadeh H, Eren B, Gurer-Orhan H Suzen, S, Özden S (2010) Novel indole-based analogs of melatonin: Synthesis and in vitro antioxidant activity studies. Molecules 15 (4): 2187–2202.

  151. Yilmaz AD, Coban T, Suzen S (2012) Synthesis and antioxidant activity evaluations of melatonin-based analogue indole-hydrazide/hydrazone derivatives. J. Enzym. Inhib. Med. Chem. 27 (3):428–436.

  152. Gurkok G, Coban T, Suzen S (2009) Melatonin analogue new indole hydrazide/hydrazone derivatives with antioxidant behavior: Synthesis and structureactivity relationships. J. Enzym. Inhib. Med. Chem. 24 (2): 506–515.

  153. Suzen S, Cihaner SS, Coban T (2012) Synthesis and comparison of antioxidant properties of indole-based melatonin analogue indole amino acid derivatives. Chem. Biol. Drug Des. 79 (1): 76–83.

  154. Reiter RJ, et al. (2015) Phytomelatonin: Assisting plants to survive and thrive. Molecules 20 (4): 7396-7437.

  155. Reiter RJ, et al. (2008) Biogenic amines in the reduction of oxidative stress: Melatonin and its metabolites. Neuro. Endocrinol. Lett. 29 (4): 391-398.

  156. Hardeland R (2014) Melatonin’s antioxidant properties: molecular mechanisms. In: Srinivasan V, Brzezinski A, Oter S, Chilcott SD, editors. Melatonin and Melatonergic Drugs in Clinical Practice. New Delhi: Springer India; 2014: 17–26. ISBN: 978-81-322-0825-9.     

  157. Dmitrzak-Weglarz M, Reszka E (2017) Pathophysiology of depression: molecular regulation of melatonin homeostasis - current status. Neuropsychobiology 76 (3): 117-129.

  158. Prado NJ, Ferder L, Manucha W, Diez ER (2018) Anti-inflammatory effects of melatonin in obesity and hypertension. Curr. Hypertens Rep. 20 (5): 45.

  159. Sarkar S, Chattopadhyay A, Bandyopadhyay, D (2021) Melatonin as a prospective metabolic regulator in pathologically altered cardiac energy homeostasis. Melatonin Res. 4 (2): 316-335.

  160. Wan XD, et al. (2013) Long-term melatonin administration improves glucose homeostasis and insulin resistance state in high-fat-diet fed rats. Open. Life Sci. 8 (10): 958-967.

  161. Owino S, Buonfiglio DDC, Tchio C, Tosini G (2019) Melatonin signaling a key regulator of glucose homeostasis and energy metabolism. Front.  Endocrinol.  (Lausanne). 10: 488.

  162. Hong F, et al. (2020) Melatonin orchestrates lipid homeostasis through the hepatointestinal circadian clock and microbiota during constant light exposure. Cells 9 (2): E489.

  163. Park WR, et al. (2022) Melatonin regulates iron homeostasis by inducing hepcidin expression in hepatocytes. Int. J. Mol. Sci. 23 (7): 3593.

  164.  Gonzalez A, Santofimia-Castaño P, Salido Gines M (2015) Melatonin, mitochondria, and Ca2+ homeostasis in the exocrine pancreas: an overview. Turk. J. Bio. 39: 801-812.

  165. Jauhari A, et al. (2020) Melatonin inhibits cytosolic mitochondrial DNA-induced neuroinflammatory signaling in accelerated aging and neurodegeneration. J. Clin. Invest. 130 (6): 3124-3136. Erratum in: J Clin Invest. (2021) 131(9).

  166. Yeung HM, Hung MW, Fung ML (2008) Melatonin ameliorates calcium homeostasis in myocardial and ischemia-reperfusion injury in chronically hypoxic rats. J.  Pineal Res. 45 (4): 373-382.

  167. Baburina Y, Lomovsky A, Krestinina O (2021) Melatonin as a potential multitherapeutic agent. J.  Pers. Med. 11 (4): 274.

  168. Dai CQ, Guo Y, Chu XY (2020) Neuropathic pain: the dysfunction of drp1, mitochondria, and ROS homeostasis. Neurotox. Res. 38 (3): 553-563. 

  169. Agil A, et al. (2021) Melatonin enhances the mitochondrial functionality of brown adipose tissue in obese-diabetic rats. Antioxidants (Basel) 10 (9): 482.

  170. Paradies G, et al. (2010) Melatonin, cardiolipin and mitochondrial bioenergetics in health and disease. J.  Pineal Res. 48 (4): 297-310.

  171. Popov LD (2020) Mitochondrial biogenesis: An update. J.  Cell Mol. Med. 24 (9): 4892-4899.

CCBY.png

This work is licensed under a Creative Commons Attribution 4.0 International License