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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: Reiter 2003 Acta Biochim Pol; 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: 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.

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.
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:

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

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.
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 cariolipin and polyunsaturated fatty acid (PUFAs), allowing to maintain an adequate structure and function and consequently preserving bioenergetic processes.

References

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
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
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
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
Reiter RJ, Tan DX, Mayo JC, Sainz RM, Leon J, Czarnocki Z (2003) Melatonin as an antioxidant: biochemical mechanisms and pathophysiological implications in humans. Acta Biochim Pol 50:1129-46. »PMID: 14740000

@@ Line 1: / Line 1: @@
 {{MitoPedia
 |abbr=aMT
-|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 at the level of mitochondria. » [[#Melatonin and attenuation of mitochondrial oxidative damage |'''MiPNet article''']]
+|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. » [[#Melatonin and attenuation of mitochondrial oxidative damage |'''MiPNet article''']]
 |info=[[Reiter 2003 Acta Biochim Pol]]; [[Acuña-Castroviejo 2014 Cell Mol Life Sci]]
 }}
@@ Line 7: / Line 7: @@
 {{MitoPedia topics}}
 __TOC__
-= Melatonin and attenuation of mitochondrial oxidative damage =
+= Melatonin and protection from mitochondrial damage =
 {{Publication
 |title=Doerrier C (2015) Melatonin and attenuation of mitochondrial oxidative damage. Mitochondr Physiol Network 2015-03-03.
@@ Line 18: / Line 18: @@
 }}
 == Pineal and extrapineal melatonin ==
-Melatonin (N-acetyl-5-methoxytryptamine, aMT) is a highly conserved molecule which is present in a broad phylogenetic taxa, including bacteria, fungi, plants, algae, invertebrate and vertebrate organisms.
+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.
+# 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.
-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 the 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 with circadian functions.
+# 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.
-However, melatonin is also produced in other organs, tissues and fluids (extrapineal melatonin). Extrapineal melatonin levels occur in much higher levels than pineal melatonin (micromolar range versus nanomolar range). The production of extrapineal melatonin occurs in the tissue when it is necessary and independently of the pineal synthesis. Moreover, extrapineal melatonin differs from pineal melatonin due to stays into the cell protecting the tissue.
-Whereas pineal melatonin has been related with chronobiotic functions, extrapineal melatonin shows mainly antioxidant and antiinflammatory actions.
 == Mechanisms of action ==
-Currently, two different mechanisms of action of melatonin have been described:
+Two different mechanisms of action of melatonin have been described:
+# Receptor-mediated mechanism: Melatonin binds to membrane receptors (such as MT1 and MT2), nuclear receptors (RZR/ROR) and cytosolic proteins (such calmodulin and calreticulin).
-) Receptor-mediated mechanism: Melatonin binds to membrane receptors (such as MT1 and MT2), nuclear receptors (RZR/ROR) and cytosolic proteins (such calmodulin and calreticulin).
+# Non receptor-mediated mechanism.
-) Non receptor-mediated mechanism.
-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. Precisely, melatonin exerts relevant functions at the level of mitochondria. Mitochondria are an important source of reactive oxygen and nitrogen species (ROS/RNS) into the cell. Mitochondria are the main target of melatonin. Here, melatonin exerts important actions protecting against mitochondrial damage.
+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.
@@ Line 43: / Line 36: @@
 Melatonin shows pleiotropic functions with a wide spectrum of properties.
-* Melatonin is a powerful antioxidant:
+=== Melatonin is a powerful antioxidant ===
-. Melatonin presents direct free radical scavenger activity. Due to its structure and its high-potential redox melatonin and its metabolites have been able to act as electron donor, scavenging ROS.
+# 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.
+# 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).
-. 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 displays an important role as anti-inflammatory molecule:
-During inflammatory diseases (such as sepsis or fibromyalgia), in mitochondria occur an induction of i-mtNOS (inducible mitochondrial isoform of nitric oxide synthase) which generates 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 produce finally an oxidative-nitrosative stress able to damage cellular structures, resulting 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, in the inflammatory process results the activation of the nuclear factor NF-kB which acts in nucleus triggering the expression of several proinflammatory genes. Melatonin inhibits the activation of NF-kB pathway.
+=== 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.
-* Melatonin exhibits oncostatic effects by different mechanisms of action. Melatonin is able to inhibit proliferation or induce apoptosis activation of tumoral cells.
+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.
-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 cardiolipid (CL) are involved in CI and CIV activities, mitochondrial supramolecular organization in supercomplexes (SC), the integrity of mitochondrial network and apoptotic process. Therefore, alterations in CL structure, content and/or acyl chains compositions show significant implications in 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.
+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 [[Respiratory complexes |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.
-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 hiperoxidative damage mediated via different 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 cariolipin and polyunsaturated fatty acid (PUFAs), allowing to maintain an adequate structure and function and consequently preserving bioenergetic processes.
-In summary, melatonin administration can counteract mitochondrial impairment mainly by decreasing ROS/RNS production, preventing LPO and hence reducing oxidative damage in relevant component of mitochondrial membranes such as CL and polyunsaturated fatty acid (PUFAs), allowing to maintain an adequate structure and function and consequently preserving bioenergetic process.
+== References ==
+# 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. »[[Acuña-Castroviejo 2014 Cell Mol Life Sci |PMID: 24554058]]
+# 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. »[[Doerrier 2014 Life Sci |PMID: 25498899]]
+# 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. »[[Lopez 2009 J Pineal Res |PMID: 19054298]]
+# 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. »[[Ortiz 2014 J Pineal Res |PMID: 25388914]]
+# Reiter RJ, Tan DX, Mayo JC, Sainz RM, Leon J, Czarnocki Z (2003) Melatonin as an antioxidant: biochemical mechanisms and pathophysiological implications in humans. Acta Biochim Pol 50:1129-46. »[[Reiter 2003 Acta Biochim Pol |PMID: 14740000]]

Difference between revisions of "Melatonin"