Melatonin: Nature's most versatile biological signal?

Melatonin is a ubiquitous molecule and widely distributed in nature, with functional activity occurring in unicellular organisms, plants, fungi and animals. In most vertebrates, including humans, melatonin is synthesized primarily in the pineal gland and is regulated by the environmental light/dark cycle via the suprachiasmatic nucleus. Pinealocytes function as 'neuroendocrine transducers' to secrete melatonin during the dark phase of the light/dark cycle and, consequently, melatonin is often called the 'hormone of darkness'. Melatonin is principally secreted at night and is centrally involved in sleep regulation, as well as in a number of other cyclical bodily activities. Melatonin is exclusively involved in signaling the 'time of day' and 'time of year' (hence considered to help both clock and calendar functions) to all tissues and is thus considered to be the body's chronological pacemaker or 'Zeitgeber'. Synthesis of melatonin also occurs in other areas of the body, including the retina, the gastrointestinal tract, skin, bone marrow and in lymphocytes, from which it may influence other physiological functions through paracrine signaling. Melatonin has also been extracted from the seeds and leaves of a number of plants and its concentration in some of this material is several orders of magnitude higher than its night-time plasma value in humans. Melatonin participates in diverse physiological functions. In addition to its timekeeping functions, melatonin is an effective antioxidant which scavenges free radicals and up-regulates several antioxidant enzymes. It also has a strong antiapoptotic signaling function, an effect which it exerts even during ischemia. Melatonin's cytoprotective properties have practical implications in the treatment of neurodegenerative diseases. Melatonin also has immune-enhancing and oncostatic properties. Its 'chronobiotic' properties have been shown to have value in treating various circadian rhythm sleep disorders, such as jet lag or shift-work sleep disorder. Melatonin acting as an 'internal sleep facilitator' promotes sleep, and melatonin's sleep-facilitating properties have been found to be useful for treating insomnia symptoms in elderly and depressive patients. A recently introduced melatonin analog, agomelatine, is also efficient for the treatment of major depressive disorder and bipolar affective disorder. Melatonin's role as a 'photoperiodic molecule' in seasonal reproduction has been established in photoperiodic species, although its regulatory influence in humans remains under investigation. Taken together, this evidence implicates melatonin in a broad range of effects with a significant regulatory influence over many of the body's physiological functions.     

Melatonin metabolism,signaling and possible roles in plants

Melatonin is a multifunctional biomolecule found in both animals and plants. In this review, the biosynthesis, levels, signaling, and possible roles of melatonin and its metabolites in plants is summarized. Tryptamine 5-hydroxylase (T5H), which catalyzes the conversion of tryptamine into serotonin, has been proposed as a target to create a melatonin knockout mutant presenting a lesion-mimic phenotype in rice. With a reduced anabolic capacity for melatonin biosynthesis and an increased catabolic capacity for melatonin metabolism, all plants generally maintain low melatonin levels. Some plants, including Arabidopsis and Nicotiana tabacum (tobacco), do not possess tryptophan decarboxylase (TDC), the first committed step enzyme required for melatonin biosynthesis. Major melatonin metabolites include cyclic 3-hydroxymelatonin (3-OHM) and 2-hydroxymelatonin (2-OHM). Other melatonin metabolites such as N¹-acetyl-N²-formyl-5-methoxykynuramine (AFMK), N-acetyl-5-methoxykynuramine (AMK) and 5-methoxytryptamine (5-MT) are also produced when melatonin is applied to Oryza sativa (rice). The signaling pathways of melatonin and its metabolites act via the mitogen-activated protein kinase (MAPK) cascade, possibly with Cand2 acting as a melatonin receptor, although the integrity of Cand2 remains controversial. Melatonin mediates many important functions in growth stimulation and stress tolerance through its potent antioxidant activity and function in activating the MAPK cascade. The concentration distribution of melatonin metabolites appears to be species specific because corresponding enzymes such as M2H, M3H, catalases, indoleamine 2,3-dioxygenase (IDO) and N-acetylserotonin deacetylase (ASDAC) are differentially expressed among plant species and even among different tissues within species. Differential levels of melatonin and its metabolites can lead to differential physiological effects among plants when melatonin is either applied exogenously or overproduced through ectopic overexpression.     

Melatonin as an antioxidant: biochemical mechanisms and pathophysiological implications in humans

This brief resume enumerates the multiple actions of melatonin as an antioxidant. This indoleamine is produced in the vertebrate pineal gland, the retina and possibly some other organs. Additionally, however, it is found in invertebrates, bacteria, unicellular organisms as well as in plants, all of which do not have a pineal gland. Melatonin's functions as an antioxidant include: a), direct free radical scavenging, b), stimulation of antioxidative enzymes, c), increasing the efficiency of mitochondrial oxidative phosphorylation and reducing electron leakage (thereby lowering free radical generation), and 3), augmenting the efficiency of other antioxidants. There may be other functions of melatonin, yet undiscovered, which enhance its ability to protect against molecular damage by oxygen and nitrogen-based toxic reactants. Numerous in vitro and in vivo studies have documented the ability of both physiological and pharmacological concentrations to melatonin to protect against free radical destruction. Furthermore, clinical tests utilizing melatonin have proven highly successful; because of the positive outcomes of these studies, melatonin's use in disease states and processes where free radical damage is involved should be increased.     

Significance of melatonin in antioxidative defense system: reactions and products

Melatonin is a potent endogenous free radical scavenger, actions that are independent of its many receptor-mediated effects. In the last several years, hundreds of publications have confirmed that melatonin is a broad-spectrum antioxidant. Melatonin has been reported to scavenge hydrogen peroxide (H(2)O(2)), hydroxyl radical (HO(.)), nitric oxide (NO(.)), peroxynitrite anion (ONOO(-)), hypochlorous acid (HOCl), singlet oxygen ((1)O(2)), superoxide anion (O(2)(-).) and peroxyl radical (LOO(.)), although the validity of its ability to scavenge O(2)(-). and LOO(.) is debatable. Regardless of the radicals scavenged, melatonin prevents oxidative damage at the level of cells, tissues, organs and organisms. The antioxidative mechanisms of melatonin seem different from classical antioxidants such as vitamin C, vitamin E and glutathione. As electron donors, classical antioxidants undergo redox cycling; thus, they have the potential to promote oxidation as well as prevent it. Melatonin, as an electron-rich molecule, may interact with free radicals via an additive reaction to form several stable end-products which are excreted in the urine. Melatonin does not undergo redox cycling and, thus, does not promote oxidation as shown under a variety of experimental conditions. From this point of view, melatonin can be considered a suicidal or terminal antioxidant which distinguishes it from the opportunistic antioxidants. Interestingly, the ability of melatonin to scavenge free radicals is not in a ratio of mole to mole. Indeed, one melatonin molecule scavenges two HO. Also, its secondary and tertiary metabolites, for example, N(1)-acetyl-N(2)-formyl-5-methoxykynuramine, N-acetyl-5-methoxykynuramine and 6-hydroxymelatonin, which are believed to be generated when melatonin interacts with free radicals, are also regarded as effective free radical scavengers. The continuous free radical scavenging potential of the original molecule (melatonin) and its metabolites may be defined as a scavenging cascade reaction. Melatonin also synergizes with vitamin C, vitamin E and glutathione in the scavenging of free radicals. Melatonin has been detected in vegetables, fruits and a variety of herbs. In some plants, especially in flowers and seeds (the reproductive organs which are most vulnerable to oxidative insults), melatonin concentrations are several orders of magnitude higher than measured in the blood of vertebrates. Melatonin in plants not only provides an alternative exogenous source of melatonin for herbivores but also suggests that melatonin may be an important antioxidant in plants which protects them from a hostile environment that includes extreme heat, cold and pollution, all of which generate free radicals.     

The Physiological Function of Melatonin in Plants

Melatonin (N-acetyl-5-methoxytryptamine), a well-known animal hormone, was discovered in plants in 1995 but very little research into it has been carried out since. It is present in different parts of all the plant species studied, including leaves, stems, roots, fruits and seeds. This brief review will attempt to provide an overview of melatonin (its discovery, presence and functions in different organisms, biosynthetic route, etc.) and to compile a practically complete bibliography on this compound in plants. The common biosynthetic pathways shared by the auxin, indole-3-acetic, and melatonin suggest a possible coordinated regulation in plants. More specifically, our knowledge to date of the role of melatonin in the vegetative and reproductive physiology of plants is presented in detail. The most interesting aspects for future physiological studies are presented.Key Words: antioxidant, auxin, flowering, growth, IAA, melatonin, plant hormone, reproductive development, rooting, vegetative developmentMelatonin (N-acetyl-5-methoxytryptamine), an “old friend” and well known as an animal hormone but “new” to plant biology is arousing great interest due to its broad distribution in the biological kingdom and the recent data on its possible physiological role in plants. Many studies on melatonin, as a phytochemical compound with potentially interesting health-related properties, have recently appeared, but no more than 15–20 papers with a plant physiological focus have been published since 1995. Besides mentioning the most interesting data on melatonin related with plants, this review will hopefully trigger more studies into this molecule to deepen our understanding of the different physiological roles that it might play in plants. We shall briefly look at the well-known function of melatonin in vertebrates, its discovery in plants and other organisms, and its presence in plants as a possible medicinal phytochemical. The joint biosynthetic pathways of melatonin and the auxin indole-3-acetic acid (IAA) will be described. Thus, we reveal the new and emerging field of melatonin studies in plants, the limited physiological data available and its possible role in plants.     

Circadian rhythms from multiple oscillators: lessons from diverse organisms

The organization of biological activities into daily cycles is universal in organisms as diverse as cyanobacteria, fungi, algae, plants, flies, birds and man. Comparisons of circadian clocks in unicellular and multicellular organisms using molecular genetics and genomics have provided new insights into the mechanisms and complexity of clock systems. Whereas unicellular organisms require stand-alone clocks that can generate 24-hour rhythms for diverse processes, organisms with differentiated tissues can partition clock function to generate and coordinate different rhythms. In both cases, the temporal coordination of a multi-oscillator system is essential for producing robust circadian rhythms of gene expression and biological activity.     

Melatonin

Melatonin, originally discovered as a hormone of the pineal gland, is produced by bacteria, protozoa, plants, fungi, invertebrates, and various extrapineal sites of vertebrates, including gut, skin, Harderian gland, and leukocytes. Biosynthetic pathways seem to be identical. Actions are pleiotropic, mediated by membrane and nuclear receptors, other binding sites or chemical interactions. Melatonin regulates the sleep/wake cycle, other circadian and seasonal rhythms, and acts as an immunostimulator and cytoprotective agent. Circulating melatonin is mostly 6-hydroxylated by hepatic P450 monooxygenases and excreted as 6-sulfatoxymelatonin. Pyrrole-ring cleavage is of higher importance in other tissues, especially the brain. The product, N1-acetyl-N2-formyl-5-methoxykynuramine, is formed by enzymatic, pseudoenzymatic, photocatalytic, and numerous free-radical reactions. Additional metabolites result from hydroxylation and nitrosation. The secondary metabolite, N1-acetyl-5-methoxykynuramine, supports mitochondrial function and downregulates cyclooxygenase 2. Antioxidative protection, safeguarding of mitochondrial electron flux, and in particular, neuroprotection, have been demonstrated in many experimental systems. Findings are encouraging to use melatonin as a sleep promoter and in preventing progression of neurodegenerative diseases.     

Melatonin restricts Pb-induced PCD by enhancing BI-1 expression in tobacco suspension cells

Melatonin is a conserved substance, which was discovered in the evolutionary distant organisms like bacteria, plants, invertebrates and vertebrates. Recent studies have shown that melatonin despite its possible role in photoperiod processes, has been found to be a direct free radical scavenger and an indirect antioxidant. In this report the impact of exogenous melatonin on the Bax inhibitor-1 (BI-1) expression level in Nicotiana tabacum L. line Bright Yellow 2 (BY-2) suspension cells exposed to lead was examined. BI-1 is a well-conserved protein in plants and animals that serves as the inhibitor of mammalian proapoptotic proteins as well as plant ROS-induced cell death. Our results showed that pretreatment with 200 nm melatonin, expressing BI-1 and fortified tobacco suspension cells against damages induced by lead. The obtained results revealed, that melatonin significantly increases BY-2 cells proliferation and protects BY-2 cells against death. Moreover, the conducted analyses showed for the first time that the protective effect of melatonin may be connected not only with its antioxidant properties but also with its direct impact on elevating BI-1 expression and lead-induced programmed cell death (PCD) restriction.     

Thermodynamic and metabolic effects on the scaling of production and population energy use

Ecosystem properties result in part from the characteristics of individual organisms. How these individual traits scale to impact ecosystem‐level processes is currently unclear. Because metabolism is a fundamental process underlying many individual‐ and population‐level variables, it provides a mechanism for linking individual characteristics with large‐scale processes. Here we use metabolism and ecosystem thermodynamics to scale from physiology to individual biomass production and population‐level energy use. Temperature‐corrected rates of individual‐level biomass production show the same body‐size dependence across a wide range of aerobic eukaryotes, from unicellular organisms to mammals and vascular plants. Population‐level energy use for both mammals and plants are strongly influenced by both metabolism and thermodynamic constraints on energy exchange between trophic levels. Our results show that because metabolism is a fundamental trait of organisms, it not only provides a link between individual‐ and ecosystem‐level processes, but can also highlight other important factors constraining ecological structure and dynamics.     

High levels of melatonin in the seeds of edible plants: possible function in germ tissue protection

The seeds of plants represent the anlage of the next generation and are vital to their existence. Melatonin has been identified in the leaves and flowers of plants but not in seeds. In this study, we examined the seeds of 15 edible plants for the presence of melatonin which was extracted using cold ethanol. Melatonin was initially identified by radioimmunoassay and subsequently quantified and confirmed using high performance liquid chromatography. The physiological concentrations of melatonin in the 15 seeds studied ranged from 2 to 200 ng/g dry weight. The highest concentrations of melatonin were observed in white and black mustard seeds. This level of melatonin is much higher than the known physiological concentrations in the blood of many vertebrates. Since the seed, particularly its germ tissue, is highly vulnerable to oxidative stress and damage, we surmise that melatonin, a free radical scavenger, might be present as an important component of its antioxidant defense system. Thus, melatonin in seeds may be essential in protecting germ and reproductive tissues of plants from oxidative damage due to ultraviolet light, drought, extremes in temperature, and environmental chemical pollutants.     

The evolution of the Wnt pathway

Wnt genes are important regulators of embryogenesis and cell differentiation in vertebrates and insects. New data revealed by comparative genomics have now shown that members of the Wnt signaling pathway can be found in all clades of metazoans, but not in fungi, plants, or unicellular eukaryotes. This article focuses on new data from recent genomic analyses of several basal metazoan organisms, providing evidence that the Wnt pathway was a primordial signaling pathway during evolution. The formation of a Wnt signaling center at the site of gastrulation was instrumental for the formation of a primary, anterior-posterior body axis, which can be traced throughout animal evolution.     

Melatonin, an underestimated natural substance with great potential for agricultural application

Melatonin (MEL) was thought to be only a neurotransmitter found in vertebrates until its detection in other organisms including plants. Although the number of publications on MEL function in plants is expanding, the knowledge of this subject is still insufficient. Among many functions which MEL performs in plants, its role as an antioxidant and a growth promoter is most supported by experimental evidence. This compound is an independent plant growth regulator and it may mediate the activities of other plant growth regulators. Due to its antioxidant properties MEL may also stabilize cell redox status and protect tissues against reactive oxygen and nitrogen species which accumulated under stressful environment. Some researchers propose that MEL could be used to improve the phytoremediation efficiency of plants against different pollutants. In this paper we show that exogenous MEL applied into the seeds could be a good biostimulator improving not only seed germination, seedling/plant growth but also crop production especially under stress conditions. We also believe that this compound can increase food quality (the aspect of functional food) and may improve human health. Since MEL is inexpensive and safe for animals and humans its application as a biostimulator could be a good, feasible and cost-effective method useful in agriculture.     

New data on biochemical mechanism of programmed senescence of organisms and antioxidant defense of mitochondria

Much evidence has recently been reported suggesting that reactive oxygen species (ROS) produced in mitochondria play a crucial role in the programmed senescence of organisms. In particular, it has been shown that antioxidants addressed to mitochondria slow down the appearance of symptoms of senescence and development of senile diseases and increase the median lifespan of various organisms from fungi to mammals. At the biochemical level, the mechanism of action of such rechargeable antioxidants as plastoquinonyldecyltriphenyl phosphonium (SkQ1) includes, in particular, prevention of oxidation of mitochondrial cardiolipin by ROS. The hormone melatonin also exhibits a number of such effects, and decrease in its level with age could explain the weakening of antioxidant protection upon aging. According to Moosmann et al., there exists a natural mechanism of antioxidant protection that, like SkQ1, is localized in the internal mitochondrial membrane and is rechargeable. It involves methionine residues in the surface regions of proteins encoded by mitochondrial DNA. It appears that in organisms with high respiratory metabolism the genetic code in the mitochondrial system of protein biosynthesis has changed. In these organisms (including some yeasts, insects, crustaceans, and vertebrates), the AUA codon codes for methionine rather than isoleucine, as in the case of synthesis of proteins encoded either in the nucleus or in mitochondria of organisms with lower rates of metabolism (other yeast species, sponges, and echinoderms). Methionine quenches ROS, being converted to methionine sulfoxide, which is re-reduced to the initial methionine by NADPH.     

Book of Abstracts

A widespread occurrence of melatonin (MEL) in plant kingdom has been reported. MEL is a highly conserved molecule occurring in evolutionary distant organisms. Its role in plants seems to be similar to that in animals. Although MEL function in plants is not well known, yet a hypothesis can be put forward that it probably functions as a night signal, coordinating responses to diurnal and photoperiodic environmental cues. It has also been suggested that MEL is an independent plant growth regulator, probably its action is analogous to IAA and it may mediate the actions of other plant growth regulators. Due to its antioxidant properties MEL may also stabilize cell red-ox status and protect them against reactive oxygen species (ROS) and other harmful environmental influence.     

The <Emphasis Type="Italic">FTO</Emphasis> Gene,Implicated in Human Obesity,Is Found Only in Vertebrates and Marine Algae

Human obesity is a main cause of morbidity and mortality. Recently, several studies have demonstrated an association between the FTO gene locus and early onset and severe obesity. To date, the FTO gene has only been discovered in vertebrates. We identified FTO homologs in the complete genome sequences of various evolutionary diverse marine eukaryotic algae, ranging from unicellular photosynthetic picoplankton to a multicellular seaweed. However, FTO homologs appear to be absent from all other completely sequenced genomes of plants, fungi, and invertebrate animals. Although the biological roles of these marine algal FTO homologs are still unknown, these genes will be useful for exploring basic protein features and could hence help unravel the function of the FTO gene in vertebrates and its inferred link with obesity in humans.     

Melatonin: A master regulator of plant development and stress responses

Melatonin is a pleiotropic molecule with multiple functions in plants. Since the discovery of melatonin in plants, numerous studies have provided insight into the biosynthesis, catabolism, and physiological and biochemical functions of this important molecule. Here, we describe the biosynthesis of melatonin from tryptophan, as well as its various degradation pathways in plants. The identification of a putative melatonin receptor in plants has led to the hypothesis that melatonin is a hormone involved in regulating plant growth,aerial organ development, root morphology, and the floral transition. The universal antioxidant activity of melatonin and its role in preserving chlorophyll might explain its anti-senescence capacity in aging leaves. An impressive amount of research has focused on the role of melatonin in modulating postharvest fruit ripening by regulating the expression of ethylene-related genes.Recent evidence also indicated that melatonin functions in the plant's response to biotic stress,cooperating with other phytohormones and wellknown molecules such as reactive oxygen species and nitric oxide. Finally, great progress has been made towards understanding how melatonin alleviates the effects of various abiotic stresses, including salt, drought, extreme temperature, and heavy metal stress. Given its diverse roles, we propose that melatonin is a master regulator in plants.     

Disruption of the melatonin rhythm in wild and farmed fish: a consequence of prolonged thyroxine administration and calcium depletion

Recent studies suggest that the pineal gland and its major product melatonin (N‐acetyl‐5‐methoxytryptamine: Mel) play a role in integration of various neural and endocrine functions. Observations indicate that Mel as a signal of photoperiod regulates a number of biological phenomena, including reproduction, day/night activity and many other physiological events associated with daily or seasonal rhythms in vertebrates, including fish. Mel has also been found to be a highly effective preventive antioxidant and free radical scavenger, protecting organism from oxidative damage. In all species examined, plasma melatonin concentration shows a diurnal rhythm, with the highest levels during the night. Our studies are focused on the cues affecting Mel synthesis capacity in wild and farmed fish. The Mel rhythm in fish can be disrupted by fluctuations in surrounding calcium concentration or by prolonged thyroxine (T4) exposure. Physiological depletion of plasma ionized calcium may limit the capacity of Mel night production in two fish species, farmed rainbow trout and wild flounder. Prolonged (2 week) exposure to high level of exogenous thyroxine (T4) results in reduced night‐time plasma Mel levels, and may thus inhibit the melatonin‐related time‐keeping system in juvenile salmon. Disruption of the daily Mel rhythm implies a reduced ability of organisms to respond properly to environmental signals, and may be a useful indicator of disturbance in physiological functions.     

New actions of melatonin and their relevance to biometeorology

 Melatonin is not only produced by the pineal gland, retina and parietal but also by various other tissues and cells from vertebrates, invertebrates, fungi, plants, multicellular algae and by unicells. In plants, many invertebrates and unicells, its concentration often exceeds that found in vertebrate blood by several orders of magnitude. The action of melatonin is highly pleiotropic. It involves firstly, direct effects, via specific binding sites in various peripheral tissues and cells of vertebrates, including immunomodulation; secondly, systemic influences on the cytoskeleton and nitric oxide formation, mediated by calmodulin; and thirdly, antioxidative protection, perhaps also in the context of photoprotection in plants and unicells. In some dinoflagellates, melatonin conveys temperature signals. On the basis of these comparisons, melatonin appears to mediate and modulate influences from several major environmental factors, such as the photoperiod, radiation intensity and temperature. Received: 18 March 1997 / Accepted: 16 July 1997     

Biogenic amines in the reduction of oxidative stress: melatonin and its metabolites

N-acetyl-5-methoxytryptamine (melatonin) is an endogenous indoleamine produced by all vertebrate organisms. Its production in the pineal gland has been extensively investigated but other organs also synthesize this important amine. Melatonin's functions in organisms are diverse. The actions considered in the current review relate to its ability to function in the reduction of oxidative stress, i.e., molecular damage produced by reactive oxygen and reactive nitrogen species. Numerous publications have now shown that not only is melatonin itself an efficient scavenger of free radicals and related reactants, but so are its by-products cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine, and others. These derivatives are produced sequentially when each functions in the capacity of a free radical scavenger. These successive reactions are referred to as the antioxidant cascade of melatonin. That melatonin has this function within cells has been observed in studies employing time lapse conventional, confocal and multiphoton fluorescent microscopy coupled with the use of appropriate mitochondrial-targeted fluorescent probes. The benefits of melatonin and its metabolites have been described in the brain where they are found to be protective in models of Parkinson's disease, Alzheimer's disease and spinal cord injury. The reader is reminded, however, that data not covered in this review has documented beneficial actions of these amines in every organ where they have been tested. The outlook for the use of melatonin in clinical trials looks encouraging given its low toxicity and high efficacy.     

Evolutionary roots of iodine and thyroid hormones in cell-cell signaling

In vertebrates, thyroid hormones (THs, thyroxine, and triiodothyronine) are critical cell signaling molecules. THs regulate and coordinate physiology within and between cells, tissues, and whole organisms, in addition to controlling embryonic growth and development, via dose-dependent regulatory effects on essential genes. While invertebrates and plants do not have thyroid glands, many utilize THs for development, while others store iodine as TH derivatives or TH precursor molecules (iodotyrosines)-or produce similar hormones that act in analogous ways. Such common developmental roles for iodotyrosines across kingdoms suggest that a common endocrine signaling mechanism may account for coordinated evolutionary change in all multi-cellular organisms. Here, I expand my earlier hypothesis for the role of THs in vertebrate evolution by proposing a critical evolutionary role for iodine, the essential ingredient in all iodotyrosines and THs. Iodine is known to be crucial for life in many unicellular organisms (including evolutionarily ancient cyanobacteria), in part, because it acts as a powerful antioxidant. I propose that during the last 3-4 billion years, the ease with which various iodine species become volatile, react with simple organic compounds, and catalyze biochemical reactions explains why iodine became an essential constituent of life and the Earth's atmosphere-and a potential marker for the origins of life. From an initial role as membrane antioxidant and biochemical catalyst, spontaneous coupling of iodine with tyrosine appears to have created a versatile, highly reactive and mobile molecule, which over time became integrated into the machinery of energy production, gene function, and DNA replication in mitochondria. Iodotyrosines later coupled together to form THs, the ubiquitous cell-signaling molecules used by all vertebrates. Thus, due to their evolutionary history, THs, and their derivative and precursors molecules not only became essential for communicating within and between cells, tissues and organs, and for coordinating development and whole-body physiology in vertebrates, but they can also be shared between organisms from different kingdoms.