Melatonin Synthesis and Function: Evolutionary History in Animals and Plants

Abstract

Melatonin is an ancient molecule that can be traced back to the origin of life. Melatonin's initial function was likely that as a free radical scavenger. Melatonin presumably evolved in bacteria; it has been measured in both α-proteobacteria and in photosynthetic cyanobacteria. In early evolution, bacteria were phagocytosed by primitive eukaryotes for their nutrient value. According to the endosymbiotic theory, the ingested bacteria eventually developed a symbiotic association with their host eukaryotes. The ingested α-proteobacteria evolved into mitochondria while cyanobacteria became chloroplasts and both organelles retained their ability to produce melatonin. Since these organelles have persisted to the present day, all species that ever existed or currently exist may have or may continue to synthesize melatonin in their mitochondria (animals and plants) and chloroplasts (plants) where it functions as an antioxidant. Melatonin's other functions, including its multiple receptors, developed later in evolution. In present day animals, via receptor-mediated means, melatonin functions in the regulation of sleep, modulation of circadian rhythms, enhancement of immunity, as a multifunctional oncostatic agent, etc., while retaining its ability to reduce oxidative stress by processes that are, in part, receptor-independent. In plants, melatonin continues to function in reducing oxidative stress as well as in promoting seed germination and growth, improving stress resistance, stimulating the immune system and modulating circadian rhythms; a single melatonin receptor has been identified in land plants where it controls stomatal closure on leaves. The melatonin synthetic pathway varies somewhat between plants and animals. The amino acid, tryptophan, is the necessary precursor of melatonin in all taxa. In animals, tryptophan is initially hydroxylated to 5-hydroxytryptophan which is then decarboxylated with the formation of serotonin. Serotonin is either acetylated to N-acetylserotonin or it is methylated to form 5-methoxytryptamine; these products are either methylated or acetylated, respectively, to produce melatonin. In plants, tryptophan is first decarboxylated to tryptamine which is then hydroxylated to form serotonin.

Keywords: antioxidant; biological rhythms; biosynthesis enzymes; endosymbiosis; evolution; melatonin; regulation of melatonin.

Figure 1

This figure illustrates the endosymbiotic origin of mitochondria and chloroplasts. α-Proteobacteria, originally phagocytized for their nutrient value by early eukaryotes eventually evolved into mitochondria. Photosynthetic cyanobacteria were likewise phagocytized by eukaryotes and eventually formed chloroplasts. Since plants have both mitochondria and chloroplasts, plant cells generally have higher concentrations of melatonin than do animal cells. Adapted from Reiter et al. (10).

Figure 2

This figure summarizes the possible evolution of various functions (not all are depicted in this figure) of melatonin. Melatonin, predictably, initially evolved in bacteria for the purpose of mitigating oxidative stress, i.e., as an antioxidant (red lines). When the bacteria were phagocytized as food by early eukaryotes, they eventually developed a mutually beneficial association with their hosts and evolved into mitochondria and chloroplasts (see Figure 1); this series of events is referred to as endosymbiosis. Subsequently, as evolution proceeded, mitochondria (animals and plants) and chloroplasts (plants) were preserved up until the present day. Thus, mitochondria and chloroplasts of every species that has ever existed or exists today, we theorize, presumably produce melatonin. This presumption is supported by recent findings which show that these organelles, in many cases, possess the necessary synthetic machinery to generate melatonin. Melatonin's role as an antioxidant in these organelles is of great importance since they are sites of major free radical production. Other colored lines, which are appropriately labeled, identify other functions of melatonin. It is essential that the time frame for these functions, as illustrated by the length of the colored lines, do not accurately depict the time of evolution of these functions. Major events in the history of the Earth are also identified. The “B” following the numbers refers to “billions of years ago.”.

Figure 3

The association of melatonin with mitochondria is predicted on the basis of the origin of these organelles as specified in the text. Current evidence suggests that melatonin is synthesized in some species in the mitochondrial matrix as illustrated here. Also, exogenously administered melatonin concentrates in the mitochondria (102), i.e., melatonin is a mitochondria-targeted agent. Given that melatonin functions as an antioxidant is particularly important in mitochondria since these organelles are a major site of free radical generation. In addition to directly neutralizing reactive oxygen species, melatonin also stimulates the antioxidant enzyme superoxide dismutase (SOD2), an action that involves an elevated level of sirtuin 3 (SIRT3) (39). Melatonin potentially enters mitochondria through the oligopeptide transporters, PEPT1/2 (103). Melatonin also influences mitochondrial membrane potential by influencing uncoupling protein (UCP). Also, melatonin from the matrix may leak out of the mitochondria to interact with the melatonin receptors, MT1 and MT2, to control the release of cytochrome c.

Figure 4

Pathways of melatonin synthesis in different plant (left) and animal (right) taxa. Depending on the organism, not all of the events necessarily take place in the chloroplasts or mitochondria of every species. For the species, plant and animal, that have been investigated, the published data provide strong evidence that these organelles are critically involved with melatonin production.

Figure 5

A summary of what is known concerning the molecular mechanism governing melatonin production in plant cells and animal cells.