Melatonin

high-resolution terminology - matching measurements at high-resolution

Melatonin

Description

Melatonin (N-acetyl-5-methoxytryptamine, aMT) is a highly conserved molecule present in unicellular to vertebrate organisms. Melatonin is synthesized from tryptophan in the pinealocytes by the pineal gland and also is produced in other organs, tissues and fluids (extrapineal melatonin). Melatonin has lipophilic and hydrophilic nature which allows it to cross biological membranes. Therefore, melatonin is present in all subcellular compartments predominantly in the nucleus and mitochondria. Melatonin has pleiotropic functions with powerful antioxidant, anti-inflammatory and oncostatic effects with a wide spectrum of action particularly at the level of mitochondria. » MiPNet article

Abbreviation: aMT

Reference: Acuña-Castroviejo 2014 Cell Mol Life Sci

Melatonin and protection from mitochondrial damage

Doerrier C (2015) Melatonin and attenuation of mitochondrial oxidative damage. Mitochondr Physiol Network 2015-03-03.

Doerrier C (2015) MiPNet

Abstract: Melatonin (aMT) is a potent antioxidant and anti-inflammatory molecule able to attenuate mitochondrial oxidative damage, preserving mitochondrial function and organization.

• O2k-Network Lab: ES Granada Acuna-Castroviejo D, AT Innsbruck Gnaiger E

Pineal and extrapineal melatonin

Melatonin (N-acetyl-5-methoxytryptamine, aMT) is a highly conserved molecule which is present in a broadrange of phylogenetic taxa, including bacteria, fungi, plants, algae, invertebrate and vertebrate organisms. Whereas pineal melatonin has been related with chronobiotic functions, extrapineal melatonin shows mainly antioxidant and antiinflammatory actions.

1. Pineal melatonin: Pineal melatonin is synthesized from tryptophan in the pinealocytes by the pineal gland. Its production is controlled by a circadian signal from suprachiasmatic nucleus (SCN). At night photoreceptors of the retina generate a potential action which finally triggers an increment in the levels and activity of arylalkylamine N-acetyltransferase (AANAT) protein. AANAT is the penultimate enzyme in melatonin synthesis. However, during the day the light maintains these photoreceptors hyperpolarized, blocking melatonin synthesis. Therefore, melatonin presents maximum levels in plasma between 2-3 am, which are 10 times higher than diurnal levels. Once synthesized, melatonin is released into the bloodstream, accessing to cellular tissues and corporal fluids. Pineal melatonin is related to circadian functions.
2. Extrapineal melatonin: Melatonin is produced in various tissues, fluids and organs other than the pineal gland. Extrapineal melatonin levels are in micromolar range and are thus much higher than the nanomolar pineal melatonin concentrations. The production of extrapineal melatonin is independent of the pineal synthesis and occurs in the tissues in a different functional context. Moreover, extrapineal melatonin differs from pineal melatonin in terms of its intracellular location and protection of the tissue.

Mechanisms of action

Two different mechanisms of action of melatonin have been described:

1. Receptor-mediated mechanism: Melatonin binds to membrane receptors (such as MT1 and MT2), nuclear receptors (RZR/ROR) and cytosolic proteins (such calmodulin and calreticulin).
2. Non receptor-mediated mechanism.

Due to its lipophilic and hydrophilic nature, melatonin can cross biological membranes. Therefore, melatonin is present in all subcellular compartments, predominantly in the nucleus and mitochondria. Melatonin exerts highly relevant functions at the level of mitochondria, which are the main target of melatonin. Mitochondria are an important source of reactive oxygen and nitrogen species (ROS/RNS) in the cell, and melatonin exerts important actions protecting against mitochondrial damage.

Main functions of extrapineal melatonin

Melatonin shows pleiotropic functions with a wide spectrum of properties.

Melatonin is a powerful antioxidant

1. Melatonin presents direct free radical scavenging activity: Due to its structure and its high redox potential melatonin and its metabolites act as electron donors, scavenging ROS.
2. Indirect antioxidant activity: Melatonin decreases ROS/RNS production, increases the expression and the activity of antioxidant systems (such as glutathione peroxidase, glutathione reductase, superoxide dismutase and catalase).

Melatonin has anti-inflammatory properties

During inflammatory diseases (such as sepsis or fibromyalgia), an induction occurs in mitochondria of i-mtNOS (inducible mitochondrial isoform of nitric oxide synthase) which causes a significant rise in nitric oxide (NO●) production and consequently an increment in peroxinitrite anion (ONOO–) levels. Both NO● and ONOO– inhibit respiratory complexes, favoring electron leak and producing finally an oxidative-nitrosative stress able to damage cellular structures, resulting in mitochondrial failure and cell death. Melatonin inhibits iNOS (cytosolic isoform of nitric oxide synthase) and i-mtNOS expression, restoring NO● levels. Accordingly, melatonin decrease RNS and ROS production, maintaining an optimal mitochondrial function.

On the other hand, inflammatory processes result in the activation of the nuclear factor NF-kB which acts in the nucleus triggering the expression of several proinflammatory genes. Melatonin inhibits the activation of the NF-kB pathway.

Melatonin exhibits oncostatic effects

Melatonin inhibits cell proliferation or induces apoptosis activation of tumoral cells by different mechanisms of action.

The lipid composition of mitochondrial membranes is relevant to maintain an adequate fluidity and consequently the organization and function of mitochondria. Important phospholipids present in mitochondrial membranes are very susceptible to the ROS attack and to the damage by lipid peroxidation (LPO). Moreover, phospholipids such as cardiolipin (CL) are involved in CI and CIV activities, mitochondrial supramolecular organization in supercomplexes (SC), the integrity of mitochondrial network and apoptotic processes. Therefore, alterations in cardiolipin structure, content and/or acyl chains compositions have significant implications on mitochondrial function. Melatonin is able to protect these mitochondrial components against oxidative and nitrosative-related damage, providing and optimal membrane fluidity which is necessary for a proper mitochondrial function.

Conclusions

Mitochondrial dysfunction plays a key role in several pathologies such as neurodegenerative, cardiovascular and inflammatory diseases, metabolic disorders, ischemia-reperfusion, hypoxia, mucositis as well as in aging. Usually, mitochondrial dysfunction in these pathophysiological conditions is caused, at least in part, by an increment in oxidative and nitrosative stress. A large body of studies support that melatonin treatment protects against hyperoxidative damage mediated via various mechanisms. Melatonin allows an optimal mitochondrial function by their direct and indirect actions.

In summary, melatonin administration can counteract mitochondrial impairment mainly by decreasing ROS/RNS production, preventing LPO and hence reducing oxidative damage of relevant components of mitochondrial membranes such as cardiolipin and polyunsaturated fatty acid (PUFAs), allowing to maintain an adequate structure and function and consequently preserving bioenergetic processes.

References

1. Ortiz F, Acuña-Castroviejo D, Doerrier C, Dayoub JC, López LC, Venegas C, García JA, López A, Volt H, Luna-Sánchez M, Escames G (2014) Melatonin blunts the mitochondrial/NLRP3 connection and protects against radiation-induced oral mucositis. J Pineal Res 58:34-49. »PMID: 25388914
2. Doerrier C, García JA, Volt H, Díaz-Casado ME, Lima-Cabello E, Ortiz F, Luna-Sánchez M, Escames G, López LC, Acuña-Castroviejo D (2014) Identification of mitochondrial deficits and melatonin targets in liver of septic mice by high-resolution respirometry. Life Sci 121:158-65. »PMID: 25498899
3. López A, García JA, Escames G, Venegas C, Ortiz F, López LC, Acuña-Castroviejo D (2009) Melatonin protects the mitochondria from oxidative damage reducing oxygen consumption, membrane potential, and superoxide anion production. J Pineal Res 46:188-98. »PMID: 19054298
4. Acuña-Castroviejo D, Carretero C, Doerrier C, López LC, García-Corzo L, Tresguerres JA, Escames G (2012) Melatonin protects lung mitochondria from aging. Age (Dordr)34:681-692. »PMID: 21614449
5. Acuña-Castroviejo D, Escames G, Venegas C, Díaz-Casado ME, Lima-Cabello E, López LC, Rosales-Corral S, Tan DX, Reiter RJ (2014) Extrapineal melatonin: sources, regulation, and potential functions. Cell Mol Life Sci 71:2997-25. »PMID: 24554058
6. Acuña-Castroviejo D, López LC, Escames G, López A, García JA, Reiter RJ (2011) Melatonin-mitochondria interplay in health and disease. Curr Top Med Chem 11:221-240. »PMID: 21244359
7. Tan DX, Manchester LC, Reiter RJ, Qi WB, Karbownik M, Calvo JR (2000) Significance of melatonin in antioxidative defense system: reactions and products. Biol Signals Recept 9:137-159. »PMID: 10899700

Melatonin and mitObesity

Work in progress by Gnaiger E 2020-01-20 linked to a preprint in preparation on BME and mitObesity.

1. Acuña-Castroviejo 2011 Curr Top Med Chem
2. Acuña-Castroviejo 2012 Age (Dordr)
3. Acuña-Castroviejo 2014 Cell Mol Life Sci
4. Agil 2015 J Pineal Res
5. Bromme 2000 J Pineal Res
6. Bromme 2008 J Pineal Res
7. Da Silva 2017 Neurotox Res
8. De Moura 2017 Neurotox Res
9. De Moura Alvorcem 2018 Mitochondrion
10. Doerrier 2014 Life Sci
11. Doerrier 2016 Mitochondrion
12. Escames 2013 Horm Mol Biol Clin Investig
13. Garcia 2015 FASEB J
14. Hardeland 2009 Biofactors
15. Jimenez-Aranda 2014 J Pineal Res
16. Kleszczynski 2018 Int J Mol Sci
17. Lopez 2009 J Pineal Res
18. Lopez 2017 PLOS ONE
19. Maarman 2016 J Appl Physiol (1985)
20. Morota 2009 Exp Neurol
21. Ortiz 2014 J Pineal Res
22. Ortiz 2015 J Pineal Res
23. Reiter 2003 Acta Biochim Pol
24. Rodriguez 2013 Int J Mol Sci
25. Sarti 2013 Int J Mol Sci
26. Scarpelli 2018 J Pineal Res
27. Tan 2000 Biol Signals Recept
28. Volt 2016 J Pineal Res
29. Tümentemur G, Altunkaynak BZ, Kaplan S (2020) Is melatonin, leptin or their combination more effective on oxidative stress and folliculogenesis in the obese rats? J Obstet Gynaecol 40:116-27. - https://www.ncbi.nlm.nih.gov/pubmed/31625776
30. Maes M, Anderson G, Betancort Medina SR, Seo M, Ojala JO () Integrating autism spectrum disorder pathophysiology: mitochondria, vitamin A, CD38, oxytocin, serotonin and melatonergic alterations in the placenta and gut. Curr Pharm Des. 2019 Nov 2. - https://www.ncbi.nlm.nih.gov/pubmed/31682209
31. Farias TDSM, Paixao RID, Cruz MM, de Sa RDCDC, Simão JJ, Antraco VJ, Alonso-Vale MIC (2019) Melatonin supplementation attenuates the pro-inflammatory adipokines expression in visceral fat from obese mice induced by a high-fat diet. Cells 8. pii: E1041. - https://www.ncbi.nlm.nih.gov/pubmed/31489938
32. Xu Z, You W, Liu J, Wang Y, Shan T (2019) Elucidating the regulatory role of melatonin in brown, white, and beige adipocytes. Adv Nutr 2019 Jul 29. pii: nmz070. - https://www.ncbi.nlm.nih.gov/pubmed/31355852
33. Shafabakhsh R, Reiter RJ, Davoodabadi A, Asemi Z (2019) Melatonin as a potential inhibitor of colorectal cancer: molecular mechanisms. J Cell Biochem 120:12216-23. - https://www.ncbi.nlm.nih.gov/pubmed/31087705
34. Dantas-Ferreira RF, Raingard H, Dumont S, Schuster-Klein C, Guardiola-Lemaitre B, Pevet P, Challet E (2018) Melatonin potentiates the effects of metformin on glucose metabolism and food intake in high-fat-fed rats. Endocrinol Diabetes Metab 1:e00039. - https://www.ncbi.nlm.nih.gov/pubmed/30815567
35. Liu K, Yu W, Wei W, Zhang X, Tian Y, Sherif M, Liu X, Dong C, Wu W, Zhang L, Chen J (2019) Melatonin reduces intramuscular fat deposition by promoting lipolysis and increasing mitochondrial function. J Lipid Res 60:767-82. - https://www.ncbi.nlm.nih.gov/pubmed/30552289
36. Karamitri A, Jockers R (2019) Melatonin in type 2 diabetes mellitus and obesity. Nat Rev Endocrinol 15:105-25. - https://www.ncbi.nlm.nih.gov/pubmed/30531911
37. Valenzuela-Melgarejo FJ, Caro-Díaz C, Cabello-Guzmán G (2018) Potential crosstalk between fructose and melatonin: a new role of melatonin-inhibiting the metabolic effects of fructose. Int J Endocrinol 2018:7515767. - https://www.ncbi.nlm.nih.gov/pubmed/30154843
38. Liu Y, Li LN, Guo S, Zhao XY, Liu YZ, Liang C, Tu S, Wang D, Li L, Dong JZ, Gao L, Yang HB (2018) Melatonin improves cardiac function in a mouse model of heart failure with preserved ejection fraction. Redox Biol 18:211-21. - https://www.ncbi.nlm.nih.gov/pubmed/30031269
39. Nabavi SM, Nabavi SF, Sureda A, Xiao J, Dehpour AR, Shirooie S, Silva AS, Baldi A, Khan H, Daglia M (2019) Anti-inflammatory effects of melatonin: a mechanistic review. Crit Rev Food Sci Nutr 59(sup1):S4-16. - https://www.ncbi.nlm.nih.gov/pubmed/29902071
40. Prado NJ, Ferder L, Manucha W, Diez ER (2018) Anti-inflammatory effects of melatonin in obesity and hypertension. Curr Hypertens Rep 20:45. - https://www.ncbi.nlm.nih.gov/pubmed/29744660
41. Fernández Vázquez G, Reiter RJ, Agil A (2018) Melatonin increases brown adipose tissue mass and function in Zücker diabetic fatty rats: implications for obesity control. J Pineal Res 64:e12472. - https://www.ncbi.nlm.nih.gov/pubmed/29405372
42. Stacchiotti A, Favero G, Giugno L, Golic I, Korac A, Rezzani R (2017) Melatonin efficacy in obese leptin-deficient mice heart. Nutrients 9 pii: E1323. - https://www.ncbi.nlm.nih.gov/pubmed/29206172
43. Szewczyk-Golec K, Rajewski P, Gackowski M, Mila-Kierzenkowska C, Wesołowski R, Sutkowy P, Pawłowska M, Woźniak A (2017) Melatonin supplementation lowers oxidative stress and regulates adipokines in obese patients on a calorie-restricted diet. Oxid Med Cell Longev 2017:8494107. - https://www.ncbi.nlm.nih.gov/pubmed/29142618
44. Rubio-González A, Bermejo-Millo JC, de Luxán-Delgado B, Potes Y, Pérez-Martínez Z, Boga JA, Vega-Naredo I, Caballero B, Solano JJ, Coto-Montes A; Members of Research Team cROS (cellular Response to Oxidative Stress) (2018) Melatonin prevents the harmful effects of obesity on the brain, including at the behavioral level. Mol Neurobiol 55:5830-46. - https://www.ncbi.nlm.nih.gov/pubmed/29086246
45. Zhou H, Du W, Li Y, Shi C, Hu N, Ma S, Wang W, Ren J (2018) Effects of melatonin on fatty liver disease: The role of NR4A1/DNA-PKcs/p53 pathway, mitochondrial fission, and mitophagy. J Pineal Res 64(1). - https://www.ncbi.nlm.nih.gov/pubmed/28981157
46. Cardinali DP, Vigo DE (2017) Melatonin, mitochondria, and the metabolic syndrome. Cell Mol Life Sci 74:3941-54. - https://www.ncbi.nlm.nih.gov/pubmed/28819865
47. Han L, Wang H, Li L, Li X, Ge J, Reiter RJ, Wang Q (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). - https://www.ncbi.nlm.nih.gov/pubmed/28658527
48. Ireland KE, Maloyan A, Myatt L (2018) Melatonin improves mitochondrial respiration in syncytiotrophoblasts from placentas of obese women. Reprod Sci 25:120-30. - https://www.ncbi.nlm.nih.gov/pubmed/28443479
49. Xu P, Wang J, Hong F, Wang S, Jin X, Xue T, Jia L, Zhai Y (2017) Melatonin prevents obesity through modulation of gut microbiota in mice. J Pineal Res 62(4). - https://www.ncbi.nlm.nih.gov/pubmed/28199741

MitoPedia: BME and mitObesity

» Body mass excess and mitObesity | BME and mitObesity news | Summary |

Term	Abbreviation	Description
BME cutoff points	BME cutoff	Obesity is defined as a disease associated with an excess of body fat with respect to a healthy reference condition. Cutoff points for body mass excess, BME cutoff points, define the critical values for underweight (-0.1 and -0.2), overweight (0.2), and various degrees of obesity (0.4, 0.6, 0.8, and above). BME cutoffs are calibrated by crossover-points of BME with established BMI cutoffs.
Body fat excess	BFE	In the healthy reference population (HRP), there is zero body fat excess, BFE, and the fraction of excess body fat in the HRP is expressed - by definition - relative to the reference body mass, M°, at any given height. Importantly, body fat excess, BFE, and body mass excess, BME, are linearly related, which is not the case for the body mass index, BMI.
Body mass	m [kg]; M [kg·x-1]	The body mass M is the mass (kilogram [kg]) of an individual (object) [x] and is expressed in units [kg/x]. Whereas the body weight changes as a function of gravitational force (you are weightless at zero gravity; your floating weight in water is different from your weight in air), your mass is independent of gravitational force, and it is the same in air and water.
Body mass excess	BME	The body mass excess, BME, is an index of obesity and as such BME is a lifestyle metric. The BME is a measure of the extent to which your actual body mass, M [kg/x], deviates from M° [kg/x], which is the reference body mass [kg] per individual [x] without excess body fat in the healthy reference population, HRP. A balanced BME is BME° = 0.0 with a band width of -0.1 towards underweight and +0.2 towards overweight. The BME is linearly related to the body fat excess.
Body mass index	BMI	The body mass index, BMI, is the ratio of body mass to height squared (BMI=M·H-2), recommended by the WHO as a general indicator of underweight (BMI<18.5 kg·m-2), overweight (BMI>25 kg·m-2) and obesity (BMI>30 kg·m-2). Keys et al (1972; see 2014) emphasized that 'the prime criterion must be the relative independence of the index from height'. It is exactly the dependence of the BMI on height - from children to adults, women to men, Caucasians to Asians -, which requires adjustments of BMI-cutoff points. This deficiency is resolved by the body mass excess relative to the healthy reference population.
Comorbidity		Comorbidities are common in obesogenic lifestyle-induced early aging. These are preventable, non-communicable diseases with strong associations to obesity. In many studies, cause and effect in the sequence of onset of comorbidities remain elusive. Chronic degenerative diseases are commonly obesity-induced. The search for the link between obesity and the etiology of diverse preventable diseases lead to the hypothesis, that mitochondrial dysfunction is the common mechanism, summarized in the term 'mitObesity'.
Healthy reference population	HRP	A healthy reference population, HRP, establishes the baseline for the relation between body mass and height in healthy people of zero underweight or overweight, providing a reference for evaluation of deviations towards underweight or overweight and obesity. The WHO Child Growth Standards (WHO-CGS) on height and body mass refer to healthy girls and boys from Brazil, Ghana, India, Norway, Oman and the USA. The Committee on Biological Handbooks compiled data on height and body mass of healthy males from infancy to old age (USA), published before emergence of the fast-food and soft-drink epidemic. Four allometric phases are distinguished with distinct allometric exponents. At heights above 1.26 m/x the allometric exponent is 2.9, equal in women and men, and significantly different from the exponent of 2.0 implicated in the body mass index, BMI [kg/m2].
Height of humans	h [m]; H [m·x-1]	The height of humans, h, is given in SI units in meters [m]. Humans are countable objects, and the symbol and unit of the number of objects is N [x]. The average height of N objects is, H = h/N [m/x], where h is the heights of all N objects measured on top of each other. Therefore, the height per human has the unit [m·x-1] (compare body mass [kg·x-1]). Without further identifyer, H is considered as the standing height of a human, measured without shoes, hair ornaments and heavy outer garments.
Length	l [m]	Length l is an SI base quantity with SI base unit meter m. Quantities derived from length are area A [m2] and volume V [m3]. Length is an extensive quantity, increasing additively with the number of objects. The term 'height' h is used for length in cases of vertical position (see height of humans). Length of height per object, LUX [m·x-1] is length per unit-entity UX, in contrast to lentgth of a system, which may contain one or many entities, such as the length of a pipeline assembled from a number NX of individual pipes. Length is a quantity linked to direct sensory, practical experience, as reflected in terms related to length: long/short (height: tall/small). Terms such as 'long/short distance' are then used by analogy in the context of the more abstract quantity time (long/short duration).
MitObesity drugs		Bioactive mitObesity compounds are drugs and nutraceuticals with more or less reproducible beneficial effects in the treatment of diverse preventable degenerative diseases implicated in comorbidities linked to obesity, characterized by common mechanisms of action targeting mitochondria.
Obesity		Obesity is a disease resulting from excessive accumulation of body fat. In common obesity (non-syndromic obesity) excessive body fat is due to an obesogenic lifestyle with lack of physical exercise ('couch') and caloric surplus of food consumption ('potato'), causing several comorbidities which are characterized as preventable non-communicable diseases. Persistent body fat excess associated with deficits of physical activity induces a weight-lifting effect on increasing muscle mass with decreasing mitochondrial capacity. Body fat excess, therefore, correlates with body mass excess up to a critical stage of obesogenic lifestyle-induced sarcopenia, when loss of muscle mass results in further deterioration of physical performance particularly at older age.
VO2max	VO2max; VO2max/M	Maximum oxygen consumption, VO2max, is and index of cardiorespiratory fitness, measured by spiroergometry on human and animal organisms capable of controlled physical exercise performance on a treadmill or cycle ergometer. VO2max is the maximum respiration of an organism, expressed as the volume of O2 at STPD consumed per unit of time per individual object [mL.min-1.x-1]. If normalized per body mass of the individual object, M [kg.x-1], mass specific maximum oxygen consumption, VO2max/M, is expressed in units [mL.min-1.kg-1].