Melatonin

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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

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

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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.
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MitoPedia: BME and mitObesity

TermAbbreviationDescription
BME and mitObesity
BME cutoff pointsBME cutoffCutoff points for body mass excess, BME cutoff points, define the critical values for underweight, overweight, obesity and various degrees of obesity. BME cutoffs are calibrated by crossover-points of BME with established BMI cutoffs. The underweight and severe underweight cutoff points are BME = -0.1 and -0.2. The overweight cutoff is BME = 0.2. Increasing degrees of obesity are defined by BME cutoffs of 0.4, 0.6, 0.8, and above.
Body fat excessBFEBody fat is conventionally expressed as BF%, which is the percentage of body fat mass relative to the total body mass. In the healthy reference population (HRP), there is zero body fat excess, 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. Although M° is identical in females and males at any given height, the fraction of body fat is higher in females than males in the HRP, hence it is reasonable that the body fat excess, BFE, - but not BF% - represents the common risk factor and indicator of obesity. Importantly, body fat excess and body mass excess, BME, are linearly related, which is not the case for the body mass index, BMI.
Body massM [kg·x-1]The body mass, M, is the mass [kg] of an individual (object) [x] and is expressed in units [kg/x]. The individual (object) is a countable quantity, therefore, the unit [x] is a dimensionless number. The SI unit for mass (of a system), m, is [kg] (1 kg = 1000 g). A system is not a countable quantity and thus is not a number. The SI symbol m is used to indicate the mass of a system or sample [kg], whereas the symbol M is used to indicate the mass of an individual (object) [kg·x-1]. Both, body mass [kg/x] and mass of a sample [kg] are extensive quantities, which depend on the size of the individual or the sample. 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. The total body mass is the sum of lean body mass and fat mass, M = ML + MF, or the sum of the reference body mass of an individual at a given height in the healthy reference population and excess body mass, M = M° + ME. The excess body mass, in turn, is the sum of excess lean and fat mass, ME = MLE + MFE. The body mass excess, BME, is normalized for the reference body mass, BME = M/M°.
Body mass excessBMEThe body mass excess, BME, is a lifestyle metric. The BME with respect to the healthy reference population, HRP, is defined as BME ΔM/M°. ΔM is the excess body mass exceeding the reference body mass, M°, in the HRP. Thus 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. The BME is expressed relative to the reference body mass for your height, H [m]. A balanced BME is BME° = 0.0 with a band width of -0.1 towards underweight and +0.2 towards overweight. Considering a height of 1.78 m, the balanced body mass is M° = 65.9 kg per individual, and overweight is reached at a weight gain of 20 % or BME = 0.2: (1+0.2)·M° = 79 kg per individual (body mass index BMI0.2 = 24.9 kg/m2). At a height of 1.84 m, the balanced body mass is M° = 72.4 kg/x, and obesity is reached at a weight gain of 40 % or BME = 0.4:(1.4·M° = 101.4 kg/x (BMI0.4 = 29.9 kg/m2).
Gnaiger 2019 MiP2019
Healthy reference populationHRPA healthy reference population, HRP, of zero underweight or overweight is considered as a standard population. The WHO Child Growth Standards on height and body mass are based on large samples in longitudinal (N=1737 children) and cross-sectional studies (N=6669) with similar numbers of girls and boys from Brazil, Ghana, India, Norway, Oman and the USA (1997-2003). Anthropometric studies carried out on adults since the 1960ies are prone to reflect the impact of high-caloric nutrition on allometric relationships, referring us to earlier time points for a HRP. The Committee on Biological Handbooks compiled a large dataset on height and body mass of healthy males from infancy to old age (CBH dataset, N=17523; Zucker 1962). The original studies were published between 1931 and 1944 and thus apply to a population (USA) before emergence of the fast-food and soft drink epidemic, and with a lifestyle demanding a balanced physical activity without the impact of local war or economic disaster on starvation.
Height of humansH [m]The height of humans, H, is given in SI units in meters [m]. Without further identifyer, H is considered as the standing height, measured without shoes, hair ornaments and heavy outer garments. The person is standing upright on a firm horizontally leveled surface. A small gap of 0.1 m (10 cm) is maintained between the heels of the feet which face straight ahead and arms at sides. The back of the head, shoulder blades, buttocks and heels are touching the wall-mounted statiometer. For facing straingt, the ear canal and cheek bone are level. The 90° head of the statiometer is lowered to press the hair flat. This SOP applies to mobile persons who can stand steadily for the measurement.
VO2maxVO2max; VO2max/MMaximum oxygen consumption, VO2max, is 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]. For conversion to SI units of amount of oxygen consumed, VO2max is multiplied by the conversion factor of 0.744 to obtain JO2max [µmol O2∙s-1.x-1].