Melatonin increases the activity of the oxidative phosphorylation enzymes and the production of ATP in rat brain and liver mitochondria (original) (raw)
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Journal of Pineal Research, 2009
Abstract: The role of melatonin in improving mitochondrial respiratory chain activity and increasing ATP production in different experimental conditions has been widely reported. To date, however, the mechanism(s) involved are largely unknown. Using high-resolution respirometry, fluorometry and spectrophotometry we studied the effects of melatonin on normal mitochondrial functions. Mitochondria were recovered from mouse liver cells and incubated in vitro with melatonin at concentrations ranging from 1 nm to 1 mm. Melatonin decreased oxygen consumption concomitantly with its concentration, inhibited any increase in oxygen flux in the presence of an excess of ADP, reduced the membrane potential, and consequently inhibited the production of superoxide anion and hydrogen peroxide. At the same time it maintained the efficiency of oxidative phosphorylation and ATP synthesis while increasing the activity of the respiratory complexes (mainly complexes I, III, and IV). The effects of melatonin appeared to be due to its presence within the mitochondria, since kinetic experiments clearly showed its incorporation into these organelles. Our results support the hypothesis that melatonin, together with hormones such as triiodothyronine, participates in the physiological regulation of mitochondrial homeostasis.
Melatonin and mitochondrial function
Life Sciences, 2004
Melatonin is a natural occurring compound with well-known antioxidant properties. In the last decade a new effect of melatonin on mitochondrial homeostasis has been discovered and, although the exact molecular mechanism for this effect remains unknown, it may explain, at least in part, the protective properties found for the indoleamine in degenerative conditions such as aging as well as Parkinson's disease, Alzheimer's disease, epilepsy, sepsis and other injuries such as ischemia-reperfusion. A common feature in these diseases is the existence of mitochondrial damage due to oxidative stress, which may lead to a decrease in the activities of mitochondrial complexes and ATP production, and, as a consequence, a further increase in free radical generation. A vicious cycle thus results under these conditions of oxidative stress with the final consequence being cell death by necrosis or apoptosis. Melatonin is able of directly scavenging a variety of toxic oxygen and nitrogen-based reactants, stimulates antioxidative enzymes, increases the efficiency of the electron transport chain thereby limiting electron leakage and free radical generation, and promotes ATP synthesis. Via these actions, melatonin preserves the integrity of the mitochondria and helps to maintain cell functions and survival. D . Synergistic effects of melatonin and deprenyl against MPTP-induced mitochondrial damage and DA depletion. Neurobiology of Aging 24 (3), 491 -500. Kilanczyk, E., Bryszewska, M., 2003. The effect of melatonin on antioxidant enzymes in human diabetic skin fibroblasts. . Modification of nitric oxide synthase activity and neuronal response in rat striatum by melatonin and kynurenine derivatives. . Structure-related inhibition of calmodulin-dependent neuronal nitric-oxide synthase activity by melatonin and synthetic kynurenines. Molecular Pharmacology 58 , 967 -975. Leist, M., Volbracht, C., Fava, E., Nicotera, P., 1998. 1-Methyl-4-phenylpyridinium induces autocrine excitotoxicity, protease activation, and neuronal apoptosis. Molecular Pharmacology 54 (5), 789 -801.
Melatonin, mitochondria, and cellular bioenergetics
Journal of Pineal Research, 2001
Aerobic cells use oxygen for the production of 90–95% of the total amount of ATP that they use. This amounts to about 40 kg ATP/day in an adult human. The synthesis of ATP via the mitochondrial respiratory chain is the result of electron transport across the electron transport chain coupled to oxidative phosphorylation. Although ideally all the oxygen should be reduced to water by a four-electron reduction reaction driven by the cytochrome oxidase, under normal conditions a small percentage of oxygen may be reduced by one, two, or three electrons only, yielding superoxide anion, hydrogen peroxide, and the hydroxyl radical, respectively. The main radical produced by mitochondria is superoxide anion and the intramitochondrial antioxidant systems should scavenge this radical to avoid oxidative damage, which leads to impaired ATP production. During aging and some neurodegenerative diseases, oxidatively damaged mitochondria are unable to maintain the energy demands of the cell leading to an increased production of free radicals. Both processes, i.e., defective ATP production and increased oxygen radicals, may induce mitochondrial-dependent apoptotic cell death. Melatonin has been reported to exert neuroprotective effects in several experimental and clinical situations involving neurotoxicity and/or excitotoxicity. Additionally, in a series of pathologies in which high production of free radicals is the primary cause of the disease, melatonin is also protective. A common feature in these diseases is the existence of mitochondrial damage due to oxidative stress. The discoveries of new actions of melatonin in mitochondria support a novel mechanism, which explains some of the protective effects of the indoleamine on cell survival.
Faseb Journal, 2001
Unilateral injection into the right substantia nigra of the catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) produces extensive loss of dopaminergic cells ('hemi-parkinsonian rat'). The pineal hormone melatonin, which is a potent antioxidant against different reactive oxygen species and has been reported to be neuroprotective in vivo and in vitro, was evaluated for potential anti-Parkinson effects in this model. Imbalance in dopaminergic innervation between the striata produced by intranigral administration of 6-OHDA results in a postural asymmetry causing rotation away from the nonlesioned side. Melatonin given systemically prevented apomorphine-induced circling behavior in 6-OHDA-lesioned rats. Reduced activity of mitochondrial oxidative phosphorylation enzymes has been suggested in some neurodegenerative diseases; in particular, selective decrease in complex I activity is observed in the substantia nigra of Parkinson's disease patients. Analysis of mitochondrial oxidative phosphorylation enzyme activities in nigral tissue from 6-OHDA-lesioned rats by a novel BN-PAGE histochemical procedure revealed a clear loss of complex I activity, which was protected against in melatonintreated animals. A good correlation between behavioral parameters and enzymatic (complex I) analysis was observed independent of melatonin administration. A deficit in mitochondrial complex I could conceivably contribute to cell death in parkinsonism via free radical mechanisms, both directly via reactive oxygen species production and by decreased ATP synthesis and energy failure. Melatonin may have potential utility in the treatment of neurodegenerative disorders where oxidative stress is a participant.-Dabbeni-Sala, F., Di Santo, S., Franceschini, D., Skaper, S. D., Giusti, P. Melatonin protects against 6-OHDA-induced neurotoxicity in rats: a role for mitochondrial complex I activity. FASEB J. 15,
Rejuvenation Research, 2016
Mitochondria play a central role in the cell physiology. Besides their classic function of energy metabolism, mitochondria are involved in multiple cell functions including energy distribution through the cell, energy/heat modulation, regulation of reactive oxygen species (ROS), calcium homeostasis and apoptosis control. Simultaneously mitochondria are the main producer and target of ROS and with the result, multiple mitochondrial diseases are related to ROS induced mitochondrial injuries. Increased free radical generation, enhanced mitochondrial inducible nitric oxide (NO) synthase activity, enhanced NO production, decreased respiratory complex activity, impaired electron transport system, and opening of mitochondrial permeability transition pore all have been suggested as factors responsible for impaired mitochondrial function. Among these, neurodegenerative diseases such as Alzheimerś disease (AD), Parkinsonś disease (PD), amyotrophic lateral sclerosis (ALS), Huntingtonś disease (HD) and aging are caused by ROSinduced mitochondrial dysfunctions. Melatonin, the major hormone of the pineal gland, also acts as an antioxidant and as a regulator of mitochondrial bioenergetic function. Melatonin is selectively taken up by mitochondrial membranes, a function not shared by other antioxidants, and thus has emerged as a major potential therapeutic tool for treating neurodegenerative disorders. Multiple in vitro and in vivo experiments have shown the protective role of melatonin for preventing oxidative stress induced mitochondrial dysfunction seen in experimental models of PD, AD, and HD. Keeping these functions into consideration, this article was framed to review the protective role of melatonin with mechanistic insights against mitochondrial diseases, and may suggest the new avenues for safe and effective treatment modalities against these devastating neurodegenerative diseases. Future insights have also been discussed.
Melatonin and human mitochondrial diseases
Journal of Research in Medical Sciences, 2017
which are a group of complications caused by mitochondrial dysfunction. Mitochondrial diseases are also caused by mutations in the mitochondria affecting mitochondrial function. Mutations in mitochondria are also facilitated by high level of oxidative stress. [15] Melatonin has been shown to play a crucial role in regulation of mitochondrial homeostasis. Melatonin, in addition to being a powerful antioxidant, decreases nitric oxide (NO) generation in mitochondria and maintains bioenergetic functions of the cell. [16,17] The purpose of the current study was to identify melatonin production, metabolism, and clinical effects in diseases related to mitochondrial dysfunction including diabetes, cancer, and diseases related to brain function. Furthermore, the mechanisms through which melatonin can exert neuroprotection against neurodegenerative disorders related to mitochondrial dysfunctions are reviewed.
Journal of Pineal Research, 2000
induced increased activity of the respiratory chain complexes I and IV can prevent mitochondrial damage induced by ruthenium red in vivo. J. Pineal Res. 2000; 28:242-248. © Munksgaard, Copenhagen Abstract: Melatonin displays antioxidant and free radical scavenger properties. Due to its ability with which it enters cells, these protective effects are manifested in all subcellular compartments. Recent studies suggest a role for melatonin in mitochondrial metabolism. To study the effects of melatonin on this organelle we used ruthenium red to induce mitochondrial damage and oxidative stress. The results show that melatonin (10 mg/kg i.p.) can increase the activity of the mitochondrial respiratory complexes I and IV after its administration in vivo in a time-dependent manner; these changes correlate well with the half-life of the indole in plasma. Melatonin administration also prevented the decrease in the activity of complexes I and IV due to ruthenium red (60 mg/kg i.p.) administration. At this dose, ruthenium red did not induce lipid peroxidation but it significantly reduced the activity of the antioxidative enzyme glutathione peroxidase, an effect also counteracted by melatonin. These results suggest that melatonin modulates mitochondrial respiratory activity, an effect that may account for some of the protective properties of the indoleamine. The mitochondria-modulating role of melatonin may be of physiological significance since it seems that the indoleamine is concentrated into normal mitochondria. The data also support a pharmacological use of melatonin in drug-induced mitochondrial damage in vivo.