Melatonin and Nitric Oxide: Two Required Antagonists for Mitochondrial Homeostasis

Abstract

The presence of nitric oxide (NO* ) in the mitochondria led to analysis of its source and functions in mitochondrial homeostasis. Studies have revealed the existence of a mtNOS isoform with similar features to nNOS, with some post-traslational modifications, although without the typical signal peptide responsible for addressing proteins to mitochondrion. This isoform may account for the physiological production of NO* related to the respiratory control. During inflammatory conditions there is an excess of NO* in the mitochondria responsible for an increase in reactive oxygen and nitrogen species in sufficient amounts to compromise mitochondrial function. These conditions led to the discovery of the presence of an inducible mtNOS isoform with kinetic properties similar to iNOS. Experiments with knockout mice lacking either nNOS or iNOS further confirmed the existence of these two mtNOS isoforms in mitochondria. Although the increase in NO* in sepsis by inducible mtNOS may have important regulatory functions including the redistribution of oxygen into other pathways under hypoxia, it causes the production of excess NO* that is deleterious for the cell. Melatonin, an endogenous antioxidant, regulates mitochondrial respiration and bioenergetics and protects mitochondria from excess NO* by controlling the activity of mtNOS.

Effect of chronic treatments with GH, melatonin, estrogens, and phytoestrogens on oxidative stress parameters in liver from aged female rats

“…Mitochondrially associated NO synthases (i.e., eNOS, nNOS, or iNOS bound to mitochondria) or mtNOS (a possibly distinct NOS) may produce NO locally at mitochondria and, thus, has the potential to regulate respiration (Giulivi et al 1998;Brown and Borutaite 2002;Acuna Castroviejo et al 2005). Both free radicals, O2 and NO, are metabolized into the mitochondrial matrix through the formation of relatively stable and non-radical species, H 2 O 2 and ONOO (Poderoso et al 1996).…”

Melatonin combats molecular terrorism at the mitochondrial level

“…As mentioned previously, this nitrogen-based reactant quickly couples with O 2 · – to form ONOO – which is highly reactive and destructive. Thus, NOS is often considered a pro-oxidative enzyme and its inhibition leads to reduced oxidative damage both at the cytosol and mitochondrial levels (Reiter et al ., 2000; Acuna-Castroviejo et al ., 2005). Melatonin reduces the activity of this enzyme when administered to experimental animals and at the same time it lessens free radical mutilation of essential molecules (Pozo et al ., 1997; Benitez-King, 2006; Escames et al ., 2004; Leon et al ., 2006).…”

“…Melatonin reduces the activity of this enzyme when administered to experimental animals and at the same time it lessens free radical mutilation of essential molecules (Pozo et al ., 1997; Benitez-King, 2006; Escames et al ., 2004; Leon et al ., 2006). In some cases, the inhibition of NOS by melatonin may contribute significantly to the total antioxidative capacity of the indoleamine particularly at the mitochondrial level (Acuna-Castroviejo et al ., 2005). …”

Migraine: Molecular Basis and Herbal Medicine

“…For example, melatonin as an imperative antioxidant is considered to be scavenger of nitric oxide and its toxic metabolite peroxynitrite (ONOO -) from body. Additionally, melatonin can indirectly lead to decrease in nitric oxide synthase activity and expression in body (Acuña-Castroviejo et al, 2005); (ii) Results of measurement of a biomarker from two separate samples can be different. For example the concentration of melatonin in urine of patients with migraine is more valuable than its plasma concentration.…”