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Abstract
Although basal and moderately elevated levels of nitric oxide are physiologically necessary and beneficial, excessive upregulations of this signaling molecule can be a cause of damage and cellular dysfunctions. In the presence of increased amounts of superoxide anions (•O2–) and carbon dioxide, peroxynitrite (ONOO–) and the peroxynitrite-CO2 adduct (ONOOCO2–) generate hydroxyl (•OH), nitrogen dioxide (•NO2) and carbonate (•CO3–) radicals, which damage biomolecules by oxidation/peroxidation, nitration and nitrosation reactions. Nitrosation also occurs with all three NO congeners (NO+, •NO, and HNO = protonated NO–), with •NO especially in combination with electron/hydrogen-abstracting compounds, or with N2O3. 3-Nitrotyrosine, found in low-density lipoprotein particles (LDL), atherosclerotic plaques, ion channels, receptors, transporters, enzymes and respirasomal subunits, is associated with numerous dysfunctions. Damage to the mitochondrial electron transport chain (ETC) is of particular significance and involves nitration, nitrosation and oxidation of proteins, cardiolipin peroxidation, and binding of •NO to ETC irons. Resulting bottlenecks of electron flux cause enhanced electron leakage which leads to elevated •O2–. In combination with high •NO, •O2– initiates a vicious cycle by generating more peroxynitrite that leads to further blockades and electron dissipation. Mitochondrial dysfunction, as induced via the •NO/peroxynitrite pathway, is of utmost importance in inflammatory diseases, especially sepsis, but also relevant to neurodegenerative and various other disorders. It may contribute to processes of aging. Melatonin, hormone of the pineal gland and product of other organs, interacts directly with reactive nitrogen species, but, more importantly, has antiinflammatory properties and downregulates inducible and neuronal NO synthases (iNOS, nNOS). It does not block moderately elevated •NO formation, but rather blunts excessive rises as occurring in sepsis and breaks the vicious cycle of mitochondrial electron leakage. The melatonin metabolite N1-acetyl-5-methoxykynuramine (AMK) forms stable nitrosation products and efficiently inhibits iNOS and nNOS, in conjunction with other antiinflammatory properties.
Highlights
The indoleamine melatonin (N-acetyl-5methoxytryptamine; Fig.1), once discovered as a pineal hormone with skin lightening properties in fish and amphibia, later identified as a major regulator of seasonal and circadian rhythms, is known to represent a highly pleiotropic compound produced in various tissues and exerting numerous, highly divergent effects [1, 2]
It is a remarkable fact that melatonin is one of the few compounds that display the potential of efficiently antagonizing mitochondrial dysfunction, as initiated and maintained by elevated nitric oxide (NO) synthesis, production of peroxynitrite and dramatically increasing electron leakage
In a normal physiological range, moderate elevations of NO are poorly affected by the indoleamine and certainly not entirely suppressed
Summary
The indoleamine melatonin (N-acetyl-5methoxytryptamine; Fig.1), once discovered as a pineal hormone with skin lightening properties in fish and amphibia, later identified as a major regulator of seasonal and circadian rhythms, is known to represent a highly pleiotropic compound produced in various tissues and exerting numerous, highly divergent effects [1, 2]. In neurons, ETC malfunction can change the mitochondrial fragmentation/fission balance, which leads to losses of peripheral mitochondria, synaptic function and connectivity [9, 14,15,16] Tyrosine nitration, another consequence of enhanced NO formation, is potentiated especially in conjunction with high CO2/HCO3– levels, which are normally present in mitochondria, but may become relevant in the cytosol or body fluids during hypoxia/hypercapnia because of impaired blood flow and in ischemia/reperfusion [17]. Another consequence of enhanced NO formation, is potentiated especially in conjunction with high CO2/HCO3– levels, which are normally present in mitochondria, but may become relevant in the cytosol or body fluids during hypoxia/hypercapnia because of impaired blood flow and in ischemia/reperfusion [17] This type of protein modification can result, among other effects, in dysfunctional reuptake of neurotransmitters that further promotes neuronal overexcitation, or, in the circulation, to modified atherosclerotic plaque proteins which are more resistant to degradation. It is a remarkable fact that melatonin is one of the few compounds that display the potential of efficiently antagonizing mitochondrial dysfunction, as initiated and maintained by elevated NO synthesis, production of peroxynitrite and dramatically increasing electron leakage
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