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Keywords:

  • cardiolipin;
  • melatonin;
  • mitochondrial physiopathology

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Mitochondria and ROS production
  5. Mitochondrial antioxidant systems
  6. Mitochondrial oxidative damage
  7. Cardiolipin and mitochondrial function
  8. Melatonin and mitochondria
  9. Melatonin and lipid peroxidation
  10. Melatonin and cardiolipin in mitochondrial physiopathology
  11. Conclusions
  12. References

Abstract:  Melatonin is a natural occurring compound with well-known antioxidant properties. Melatonin is ubiquitously distributed and because of its small size and amphiphilic nature, it is able to reach easily all cellular and subcellular compartments. The highest intracellular melatonin concentrations are found in mitochondria, raising the possibility of functional significance for this targeting with involvement in situ in mitochondrial activities. Mitochondria, the powerhouse of the cell, are considered to be the most important cellular organelles to contribute to degenerative processes mainly through respiratory chain dysfunction and formation of reactive oxygen species, leading to damage to mitochondrial proteins, lipids and DNA. Therefore, protecting mitochondria from oxidative damage could be an effective therapeutic strategy against cellular degenerative processes. Many of the beneficial effects of melatonin administration may depend on its effect on mitochondrial physiology. Cardiolipin, a phospholipid located at the level of inner mitochondrial membrane is known to be intimately involved in several mitochondrial bioenergetic processes as well as in mitochondrial-dependent steps of apoptosis. Alterations to cardiolipin structure, content and acyl chain composition have been associated with mitochondrial dysfunction in multiple tissues in several physiopathological situations and aging. Recently, melatonin was reported to protect the mitochondria from oxidative damage by preventing cardiolipin oxidation and this may explain, at least in part, the beneficial effect of this molecule in mitochondrial physiopathology. In this review, we discuss the role of melatonin in preventing mitochondrial dysfunction and disease.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Mitochondria and ROS production
  5. Mitochondrial antioxidant systems
  6. Mitochondrial oxidative damage
  7. Cardiolipin and mitochondrial function
  8. Melatonin and mitochondria
  9. Melatonin and lipid peroxidation
  10. Melatonin and cardiolipin in mitochondrial physiopathology
  11. Conclusions
  12. References

Melatonin (N-acetyl-5-methoxytryptamine), is a highly conserved molecule found in organism from unicells to vertebrates [1, 2]. Melatonin has pleiotropic bioactivities that encompass numerous endocrinologic and behavioral processes [3–5]. Chemically, melatonin and its metabolites can function as endogenous free-radical scavengers and broad-spectrum antioxidants [6–11]. Because of its small size and amphiphilic nature, melatonin reaches easily all cellular and subcellular compartments [12]. The highest intracellular melatonin concentrations may be in mitochondria [13], raising the possibility of functional significance for this targeting with involvement in situ in mitochondrial activities. Most of the beneficial consequences resulting from melatonin administration may depend on its effect on mitochondrial physiology [14–16].

Mitochondria are considered the main intracellular source of reactive oxygen species (ROS) as well as the major target of free radical attach. ROS are generated at very low levels during mitochondrial respiration under normal physiological conditions, while the level of these oxidants increases in several pathological conditions and aging. ROS produced by the mitochondrial respiratory chain attach mitochondrial constituents including proteins, lipids and mitochondrial DNA. ROS-induced alterations to mitochondrial membrane constituents may lead to a decline in the bioenergetic function of mitochondria and this may be a contributory factor in a variety of pathological conditions including heart ischemia/reperfusion, aging and age-related cardiovascular and neurodegenerative diseases [17–19]. The protective effect of melatonin against these diseases may be explained, at least in part, on its antioxidant and free-radical scavenging properties, thus preserving the stability, integrity and function of mitochondrial membranes [14–16, 20–22].

Mitochondrial membrane phospholipids play a causal role in aging and other pathological conditions by modulating oxidative stress and molecular integrity. Among phospholipid species, cardiolipin (CL) has interesting chemical and structural characteristics, being highly acid and having a head group (glycerol) that is esterified to phosphatidylglyceride backbone fragments. CL has also a highly specialized physiological distribution, being almost exclusively located in the inner mitochondrial membrane where it is biosynthesized [23–25]. Growing evidence indicates that CL is involved in the regulation of several mitochondrial bioenergetic processes, optimizing the activity of key mitochondrial inner membrane proteins involved in oxidative phosphorylation [26–28]. Alterations to CL structure, content and acyl chain composition are responsible for mitochondrial dysfunction in multiple tissues in a variety of physiopathological settings [29–34]. Because of its high content of unsaturated fatty acids and to its location near to the site of ROS production, CL is particularly prone to peroxidative attack by ROS. CL peroxidation has been shown to play a critical role in several physiopathological situations [35–38] as well as in cell death [39–42]. Oxidation/depletion of CL would negatively impact the biochemical function of mitochondrial membranes, leading to cellular dysfunction and eventually cell death. Thus, pharmacological strategies able to counteract CL peroxidation would be particularly useful in preventing mitochondrial dysfunction. Recently, we have shown that melatonin prevents CL oxidation in mitochondria both under in vitro or in vivo conditions [20–22]. Because of the central role played by CL in mitochondrial bioenergetics, the protective effect of melatonin on CL oxidation may have important implications in mitochondrial physiopathology. In this review, we discuss the protective effects of melatonin against mitochondrial dysfunction and diseases in relation to CL alterations.

Mitochondria and ROS production

  1. Top of page
  2. Abstract
  3. Introduction
  4. Mitochondria and ROS production
  5. Mitochondrial antioxidant systems
  6. Mitochondrial oxidative damage
  7. Cardiolipin and mitochondrial function
  8. Melatonin and mitochondria
  9. Melatonin and lipid peroxidation
  10. Melatonin and cardiolipin in mitochondrial physiopathology
  11. Conclusions
  12. References

Mitochondria are considered the main source of ROS production. It is estimated that approximately 0.2–2% of the oxygen taken up by cell is converted by mitochondria to ROS mainly through the production of superoxide anion [43]. Mitochondria consume 80–90% of a cell’s oxygen to support oxidative phosphorylation, the major system in cell that harnesses energy from the oxidation of fuels for adenosine 5′-triphosphate (ATP) production. Oxidative phosphorylation however comes with additional cost, the production of potentially harmful ROS. Within mitochondria, the electron transport chain is the main source of ROS. The primary ROS generated into the mitochondria is superoxide anion (O2·), which is then converted to hydrogen peroxide H2O2 by spontaneous dismutation or by superoxide dismutase (SOD). Hydrogen peroxide in turn is broken down into water by glutathione peroxidase or catalase; if this does not occur, H2O2 can undergo the Fenton reaction in the presence of divalent cations such as iron to produce hydroxyl radical (HO·), which is highly harmful to mitochondrial biomolecules.

The site of ROS production along the respiratory chain has been the subject of many studies. The two major sites of O2· are complex I and complex III. At complex I (NADH-coenzyme Q reductase), the sites are thought to be the iron–sulfur centers [44, 45] or the ‘active site flavine’ [46]. Based on inhibitor studies in heart mitochondria, the site of O2· production at complex III (bc1 complex) is likely the unstable ubisemiquinone molecules [47, 48] or the cytochrome b [49]. The production of O2· at complex I is widely thought to occur at the matrix site of the inner membrane. At complex III, O2· is released to both the matrix and the cytosolic sides of the mitochondria. The relative contributions of complex I and III to ROS production appear also to be dependent on types of tissues, species and experimental conditions [48]. The rate of ROS generation is affected by mitochondrial metabolic state. O2· production is highest under state 4 condition, when oxygen consumption is low and proton motive force is high and complexes of the electron transport chain are in reduced state [50, 51]. It should be acknowledged that ROS are also produced to a lesser extent outside of the mitochondrion. Examples of extra-mitochondrial ROS-producing reactions include xanthine oxidase, D-amino oxidase, the P-450 cytochromes and proline and lysine hydroxylase.

Mitochondria can also produce nitric oxide (NO·) from mitochondrial nitric oxide synthase [52, 53], which can be converted to various reactive nitrogen species (RNS) such as nitroxyl anion (NO) or the toxic peroxynitrite (ONOO). The oxidizing reactivity of ONOO is generally considered equivalent to that of ·OH [54]. Mitochondrial production of ROS is also modulated by endogenous NO·. At low levels, NO can increase O2· and H2O2 production by modulating the rate of oxygen consumption at the cytochrome c oxidase level [55], whereas at high levels, NO· inhibits H2O2 production by reacting with O2· resulting in ONOO formation [56].

Mitochondrial antioxidant systems

  1. Top of page
  2. Abstract
  3. Introduction
  4. Mitochondria and ROS production
  5. Mitochondrial antioxidant systems
  6. Mitochondrial oxidative damage
  7. Cardiolipin and mitochondrial function
  8. Melatonin and mitochondria
  9. Melatonin and lipid peroxidation
  10. Melatonin and cardiolipin in mitochondrial physiopathology
  11. Conclusions
  12. References

Mitochondria are equipped with an impressive array of enzymatic and nonenzymatic antioxidant defence systems poised to detoxify the ROS, mainly produced by the electron transport chain. Nonenzymatic components of the system include hydrophilic and lipophilic radical scavengers, e.g., cytochrome c, alpha-tocopherol, ascorbate, ubiquinone and glutathione. Mitochondria possess also a special mechanism called mild uncoupling that prevents a marked increase in membrane potential and hence O2· formation. Enzymatic components of the antioxidant systems include manganese-superoxide dismutase (Mn-SOD), catalase, glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase. Within the mitochondrial matrix, Mn-SOD converts O2· to H2O2, which can be further metabolized by glutathione peroxidase (Gpx I) and peroxiredoxine (Prx III) or diffuse from the mitochondria into the cytosol. O2· cannot diffuse through mitochondrial membranes except in the protonated form, which constitute only a very small fraction of the O2· pool at physiological pH [57]. Part of the O2· produced by the mitochondrial respiratory chain can be released into the inner membrane space where it can be converted to H2O2 by Cu-Zn SOD. The O2· present in the intermembrane space might be scavenged by the cytochrome c or diffuse into the cytosol through the voltage-dependent anion channel (VDAC) [58]. O2· may also react with nitric oxide (NO) to form highly reactive ONOO. Glutathione (GSH) and multiple GSH-linked antioxidant enzymes exert also an important mitochondrial antioxidant protection. Among GSH-linked enzymes involved in mitochondrial antioxidant defence are Gpx 1 located predominantly in the cytosol and Gpx 4, also known as phospholipid hydroperoxide glutathione peroxidase, which is membrane associated with a fraction localized to the mitochondria, possibly at the contact sites of the two membranes. These enzymes catalyzed the reduction of H2O2 and of lipid hydroperoxides. Gpx 4 reduces hydroperoxide groups on phospholipids, lipoproteins and cholesteryl esters. Gpx 4 is considered to be the primary enzymatic defence mechanism against oxidative damage to cellular membranes.

Mitochondrial oxidative damage

  1. Top of page
  2. Abstract
  3. Introduction
  4. Mitochondria and ROS production
  5. Mitochondrial antioxidant systems
  6. Mitochondrial oxidative damage
  7. Cardiolipin and mitochondrial function
  8. Melatonin and mitochondria
  9. Melatonin and lipid peroxidation
  10. Melatonin and cardiolipin in mitochondrial physiopathology
  11. Conclusions
  12. References

Mitochondria appear to be the most powerful intracellular source of ROS. The steady state concentration of O2· in the mitochondrial matrix is about 5- to 10- fold higher than that in the cytosol [59]; therefore, mitochondria might also be a primary target for the damaging effects of ROS. The interaction of diverse macromolecules with ROS impairs the bioenergetics and function of these organelles and directly affects cell viability and triggers cell death.

Oxidative damage and modification of proteins is one of the hallmarks of aging and several pathological conditions in biological systems [60]. The degree of oxidative damage to proteins depends on several factors such as the nature and relative location of the source of an oxidant, the proximity of the radical-oxidant to a protein target and nature and concentration of available antioxidant enzymes and compounds. An important mechanism of O2· toxicity is the direct oxidation and inactivation of iron-sulfur (Fe-S) proteins such as aconitase, a mitochondrial enzyme that catalyzes the isomerization of citrate to isocitrate in Krebs cycle. Prolonged exposure of mitochondria to oxidants results in disassembly of the [4Fe-4S]2+ cluster, carbonylation and degradation of the enzyme [61], potentially establishing the link between oxidative stress and enzyme inactivation, as detected during cardiac ischemia/reperfusion injury [62]. In addition, O2· can inactivate several iron-sulfur proteins, such as complex I (NADH-dehydrogenase).

One important target of ROS is mtDNA, which encodes thirteen polypeptides, twenty-two transfer RNAs and two ribosomal RNAs, all of which are essential for electron transport and ATP generation by oxidative phosphorylation. This requires the assembly of the protein products of both the mitochondrial and nuclear genomics into functional respiratory complexes. MtDNA, therefore, represents a critical cellular target for oxidative damage that could lead to lethal cell injury through the disruption of electron transport, mitochondrial membrane potential and ATP generation. MtDNA is especially susceptible to attack by ROS because of the close proximity to the electron transport chain, the major locus for free radical production, and lack of protective histones. Oxidative damage induced by ROS is probably a major source of mitochondrial genomic instability responsible for the respiratory dysfunction. This instability of mtDNA is thought to be one of the most important factors in aging [63].

In addition to mtDNA and proteins, mitochondrial membrane lipids are highly susceptible to oxidative damage. Phospholipids are the most abundant lipid components of the cellular and subcellular membranes, including mitochondria. At the mitochondrial level, phospholipids play multiple roles: they define the essential membrane permeability barrier, modulate the functional properties of membrane-associated activities, and provide a matrix for the assembly and function of a variety of catalytic processes. Polyunsaturated fatty acids (PUFAs) are essential components of mitochondrial phospholipids. The presence of a methylene group between two double bonds renders the PUFAs particularly sensitive to ROS-induced damage. The sensitivity to oxidation increases exponentially as a function of the number of double bonds per fatty acid molecule [64]. Consequently, the high concentration of PUFAs in mitochondrial phospholipids not only makes them prime targets for reactions with oxidizing agents but also enables them to participate in long free-radical chain reactions generating hydroperoxides as well as endoperoxides which undergo fragmentation to produce a broad range of reactive intermediates, among them malondialdehyde (MDA) and the most reactive, 4-hydroxy-trans-2-nonenal (HNE). Peroxidation of membrane phospholipids is considered one of the major causes of mitochondrial dysfunction in a variety of physiopathological situations and aging. In fact, peroxidation alters the structure of membrane phospholipids, which can disrupt the structural organization of the lipid double layer, altering membrane fluidity and permeability, thereby affecting respiration and oxidative phosphorylation, inner membrane barrier properties, maintenance of mitochondrial membrane potential and mitochondrial Ca2+ buffer capacity [65].

Among phospholipid species, CL molecules are particularly susceptible to oxidation because of their high content of unsaturated fatty acids, particularly linoleic acid in heart and liver or docosanoic acid in brain tissue mitochondria [42]. The presence of a methylene group between two double bonds renders these fatty acids sensitive to ROS-induced damage. CL peroxidation is considered to proceed via a sequence of steps including the abstraction of a hydrogen atom from linoleic acid, forming an alkyl radical (CL·), followed by a rapid addition of oxygen to form the peroxyl radical (CLOO·) and then formation of a hydroperoxide (CLOOH) via abstraction of a hydrogen from another acyl chain; as a consequence, the reaction is repeated and the whole process continues in a free-radical chain reaction. Furthermore, CL molecules are considered preferential targets for ROS attack because of the fact that these molecules are located in the inner mitochondrial membrane near the site of ROS production that is represented by the respiratory chain complexes I and III. Normal CL and its oxidized form can be measured directly by a normal-phase HPLC technique with UV detection at 206 and 235 nm (indicative of conjugated dienes), respectively [66, 67]. Using this technique, we found a loss of CL in mitochondria isolated from heart and brain tissue of aged animals [68, 69], associated with an increase in the level of oxidized CL. An oxidation-induced depletion of CL was also found in heart mitochondria isolated from ischemic and ischemic/reperfused rat heart [32, 36].

Cardiolipin and mitochondrial function

  1. Top of page
  2. Abstract
  3. Introduction
  4. Mitochondria and ROS production
  5. Mitochondrial antioxidant systems
  6. Mitochondrial oxidative damage
  7. Cardiolipin and mitochondrial function
  8. Melatonin and mitochondria
  9. Melatonin and lipid peroxidation
  10. Melatonin and cardiolipin in mitochondrial physiopathology
  11. Conclusions
  12. References

Cardiolipin is a structurally unique dimeric phospholipid associated with membranes designed to generate an electrochemical gradient that is used to produce ATP. Such membranes include the bacterial plasma membrane [70] and the inner mitochondrial membrane [23, 26]. The mitochondrial inner membrane has an unusually high 3–4:1 protein lipid ratio, while the protein:lipid ratio of the mitochondrial outer membrane is approximately 1–1.6:1 [71]. This ubiquitous and intimate association between CL and energy-transducing membranes suggests an important role of CL in bioenergetic processes. CL has been shown to interact with a number of inner mitochondrial membrane proteins [25–28, 42]. The list of proteins that bind CL with high affinity is long and includes, among others, the electron transport chain complexes, involved in oxidative phosphorylation. Indeed, CL is required for optimal activity of complex I (NADH ubiquinone oxidoreductase) [72], Complex III (ubiquinone cytochrome c oxidoreductase) [73], complex IV (cytochrome c oxidase) [74] and complex V (ATP synthase) [75]. Crystallographic studies have shown the presence of a few tightly bound CL molecules in each of the crystal structures of the complex III, complex IV and ADP/ATP carrier [76]. These results suggest that CL is an integral component of these proteins, the presence of which is critical to folding.

Cardiolipin seems to facilitate the association and stabilization of respiratory chain complexes into ‘supercomplexes’ [77, 78]. Such supercomplexes formation is thought to improve the efficiency of oxidative phosphorylation by eliminating the need for diffusion of substrates and products between individual electron transport chain components. CL is also required for the interaction between ADP/ATP carrier proteins and respiratory supercomplexes [79]. In addition, CL is required for optimal activity of a number of mitochondrial anion carrier proteins such as adenine nucleotide translocator (ANT) [80], and carnitine-acylcarnitine, citrate, phosphate and pyruvate carriers [26, 27, 42]. However, it is not clear how CL contributes to full catalytic activity of these enzymes and carrier proteins. The importance of this phospholipid may result from its unique large head group carrying two negative charges, requiring a specific and tightly interacting binding site, which may stabilize a protein domain in a clamp-like manner [81]. Moreover, CL is suggested to function, with the phosphate head groups, as a proton trap, restricting pumped protons within its head group domain, thus providing the structural basis for mitochondrial membrane potential and supplying protons for the ATP synthase [82].

Because of the central role of CL in mitochondrial bioenergetics, it could be predicted that any alteration in the CL structure, content and acyl chain composition may result in mitochondrial dysfunction with subsequent implications in mitochondrial physiopathology. Alterations in mitochondrial CL profile may occur mainly as consequence of, (i) loss in the CL content, because of changes in the CL synthase activity, (ii) changes in acyl chain composition because of altered CL remodeling and (iii) CL peroxidation because of ROS attack.

Changes in mitochondrial CL content, because of alterations in CL synthase activity, have been reported in rat heart from hypo- and hyperthyroid animals [42]. These changes are responsible, at least in part, for the changes in several mitochondrial bioenergetic parameters, such as the decrease in the activity of anion carrier proteins and of cytochrome c oxidase. The specific role of CL loss in the reduced activity of cytochrome c oxidase was demonstrated by the capability of exogenous CL-liposomes to restore the normal activity of this enzyme complex when added to hypothyroid mitochondria.

Changes in fatty acid composition of CL, because of aberrant CL remodeling (replacing one fatty acid with another), are involved in Barth syndrome, a human infantile cardiomyopathy [83–85]. Barth syndrome is an X-linked disease characterized by cardiomyopathy, neutropenia, muscle weakness and loss of mitochondrial function. This disease appears to be linked to a defect in the TAZ gene, which codes for a group of proteins called tafazzin [86]. The tafazzin are phospholipid acyl transferases involved in CL remodeling. Patients with Barth syndrome exhibit a loss in tetralynoleilcardiolipin with an increase in monolysocardiolipin caused by a mutation of the tafazzin gene leading to an aberrant CL remodeling [85]. It is worth mentioning that aberrant respiratory supercomplexes were observed in fibroblasts derived from patients with Barth syndrome [87].

The production of ROS leads to primary reaction and damage in the immediate surrounding of where these reactive species are produced, by virtue of their high chemical reactivity. Therefore, the effect of these reactive species should be greatest at the mitochondrial membrane constituents. CL is particularly prone to ROS attack because of its high content of unsaturated fatty acids and its location near to the site of ROS production. Emerging insights have linked CL oxidation/depletion to alterations of several biochemical parameters involved in mitochondrial bioenergetics in various tissues of animals under a variety of diseases and physiopathological settings, including heart ischemia/reperfusion, hyper- and hypothyroid states, nonalcoholic fatty liver disease and diabetes [reviewed in 33, 42].

Mitochondrial ROS generation occurs, in part, during heart ischemia and more abundantly during reperfusion. A loss of CL, because of ROS-induced peroxidation, in heart following ischemia/reperfusion is well documented [32, 36]. The peroxidation of CL appears to be responsible, at least in part, for the loss of the activity of respiratory chain complexes (I, III and IV) and for mitochondrial dysfunction and subsequently heart injury [32, 35, 36]. In addition, it has been reported that mitochondrial damage, because of CL peroxidation and complex III dysfunction, during ischemia, sets the stage for mitochondrial-driven cardiomyocyte injury during reperfusion in the aged heart [37].

Melatonin and mitochondria

  1. Top of page
  2. Abstract
  3. Introduction
  4. Mitochondria and ROS production
  5. Mitochondrial antioxidant systems
  6. Mitochondrial oxidative damage
  7. Cardiolipin and mitochondrial function
  8. Melatonin and mitochondria
  9. Melatonin and lipid peroxidation
  10. Melatonin and cardiolipin in mitochondrial physiopathology
  11. Conclusions
  12. References

In vitro and in vivo experiments have shown that melatonin can influence mitochondrial homeostasis [14–16, 88]. Melatonin is a highly lipophilic molecule that crosses cell membranes to easily reach subcellular compartments, including mitochondria where it seems to accumulate in high concentrations [13]. In addition, melatonin stabilizes mitochondrial inner membrane [89] thereby improving electron transport chain (ETC.) activity [90]. Melatonin reportedly increases the activity of the brain and liver mitochondrial respiratory complexes I and IV in a time-dependent manner, whereas the activities of complexes II and III were not affected [91]. Melatonin administration also prevented the reduction in the activity of complexes I and IV because of mitochondrial damage and oxidative stress induced by ruthenium red administration in rats [92]. Other studies performed with submitochondrial particles obtained from rat brain and liver also show that melatonin influences complex I and IV in a concentration-dependent manner [92]. Melatonin at a concentration 1 nm significantly increases the activity of complexes I and IV in rat liver mitochondria, whereas 10–100 nm melatonin stimulated the activities of these complexes in brain mitochondria. The effects on complex I were also studied using BN-PAGE histochemical procedure to measure changes in its activity induced by melatonin. This study documented the increase of complex I activity after melatonin treatment. The effect of melatonin in regulating the activity of complexes I and IV likely do not only relay on the antioxidant role of the indoleamine. The high redox potential of melatonin 0.94 V [93] suggests that melatonin may interact with the complexes of the ETC. and may donate and accept electrons thereby increasing electron flow, an effect not possessed by other antioxidants.

Other studies revealed another effect of melatonin on mitochondrial function. Experiments carried out in isolated mitochondria demonstrate that melatonin protected the mitochondria from oxidative damage, reducing 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 [94]. 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). These effects of melatonin probably depend on a direct action of the indoleamine in the mitochondria, because these organelles are able to take up the melatonin in the concentration-dependent manner. This ability of the mitochondria to accumulate melatonin is of great pharmacological interest because it means that after exogenous administration in vivo, melatonin enters the mitochondria to exert its beneficial action.

Melatonin and lipid peroxidation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Mitochondria and ROS production
  5. Mitochondrial antioxidant systems
  6. Mitochondrial oxidative damage
  7. Cardiolipin and mitochondrial function
  8. Melatonin and mitochondria
  9. Melatonin and lipid peroxidation
  10. Melatonin and cardiolipin in mitochondrial physiopathology
  11. Conclusions
  12. References

Polyunsaturated fatty acids (PUFA) and their metabolites have a variety of physiological roles including energy provision, membrane structure, cell signaling and regulation of gene expression. PUFA are essential components in higher eukaryotes that confer fluidity, flexibility and selective permeability to cellular membranes. Peroxidation of PUFAs in lipid bilayer membranes, including mitochondria, causes loss of fluidity, collapse in membrane potential, increased permeability to protons and calcium ions and subsequently breakdown of cell membranes because of cellular deformities and destabilization. Membrane phospholipids are particularly susceptible to oxidation not only because of their highly PUFAs content but also because of their association in the cell membrane with nonenzymatic and enzymatic systems capable of generating pro-oxidant free radical species.

Many studies demonstrate the protective effect of melatonin and its derivatives on lipid peroxidation induced by oxidative stress in mitochondrial membranes [95]. Melatonin has been shown to scavenge the peroxyl radical (LOO·) [96, 97], the latter being produced during lipid peroxidation and being sufficiently reactive to propagate the chain reaction. The efficacy of melatonin as a LOO· scavenger was evaluated by measuring inhibition of metal ion-, radiation- or human macrophage- mediated oxidation of human low-density lipoprotein [98]. According to Pieri et al. [96, 99], melatonin is more effective than vitamin E in neutralizing LOO· and inhibiting lipid peroxidation, although this claim has not been confirmed by others [100]. It is presumed that melatonin achieves this high degree of lipid protection by interfering with the radicals that initiate this process, especially the ·OH and ONOO-, and by positioning itself among the membrane lipids in such a way as to impede the oxidation of the polyunsaturated fatty acids [101]. In vitro assays showed that after incubation of rat brain homogenates, brain and liver microsomes and mitochondria in an ascorbate-Fe2+ system, lipid peroxidation was found to be lowered in those membranes incubated in the presence of melatonin [102]. Melatonin has been found to protect against lipid peroxidation in many experimental models [103, 104]. Melatonin and its derivatives could reduce Fe2+-induced lipid peroxidation and necrotic cell damage in the rat hippocampus in vivo [105].

The in vitro antioxidant effect of melatonin has been evaluated on linoleate oxidation initiated by HO· free radical generated by water gamma radiolysis [106]. Using linoleate micelles as lipid model, two index of peroxidation have been measured, i.e. conjugated dienes and hydroperoxides. The results obtained in this study demonstrate that melatonin displays strong in vitro LOO· -scavenging properties as shown by its inhibitory effect on the radiation-induced peroxidation of linoleate.

Cardiolipin is particularly rich in unsaturated fatty acids, (approximately 80% represented by linoleic acid in heart tissue) and in addition it is located near to the sites of ROS production. Thus, CL molecules are particularly susceptible to peroxidation. Recently, we have studied the ability of melatonin to prevent CL peroxidation in isolated mitochondria [20, 21, 68]. To induce CL peroxidation in mitochondria, these organelles were treated with t-butylhydroperoxide (t-BuOOH), a lipid-soluble hydroperoxide that closely resembles endogenous lipid hydroperoxides generated during oxidative stress. Exposure of rat heart and brain mitochondria to t-BuOOH and micromolar concentrations of copper ions resulted in a loss of CL content and in an increase in the level of oxidized CL. Melatonin, at micromolar concentration, prevented the oxidation/depletion of CL. This inhibitory effect of melatonin on CL oxidation in mitochondria can be reasonably explained by its ability to inhibit the peroxidation of linoleic fatty acid constituents of mitochondrial CL molecules.

Emerging insights have linked CL oxidation/depletion to mitochondrial dysfunction associated with a variety of diseases and physiopathological settings including ischemia/reperfusion and aging and other degenerative diseases [33, 42]. CL oxidation is also emerging as a key player in the regulation of several of the mitochondrial steps of cell death and in mitochondrial dynamics [39–42]. Therefore, the ability of melatonin to prevent CL oxidation may have important implications in mitochondrial physiopathology.

Melatonin and cardiolipin in mitochondrial physiopathology

  1. Top of page
  2. Abstract
  3. Introduction
  4. Mitochondria and ROS production
  5. Mitochondrial antioxidant systems
  6. Mitochondrial oxidative damage
  7. Cardiolipin and mitochondrial function
  8. Melatonin and mitochondria
  9. Melatonin and lipid peroxidation
  10. Melatonin and cardiolipin in mitochondrial physiopathology
  11. Conclusions
  12. References

Heart ischemia/reperfusion

Ischemia/reperfusion (I/R) is a common problem encountered in a variety of clinical situations, particularly organ transplantation. I/R results in damage that may affect cell viability and lead to organ failure. I/R injury involves a complex cascade of events, including loss of energy, derangement of the ionic homeostasis, production of ROS and cell death. There is ample evidence demonstrating that ROS play an important role in producing lethal cell injury associated with heart ischemia/reperfusion. The mechanisms for the enhanced ROS generation and cellular and subcellular target of ROS attack are not well established. One of the main sources of ROS in cardiomyocytes during ischemia and early reperfusion may be a defect in the mitochondrial ETC. activity, particularly at the level of complexes I and III, the main sites of ROS production. As major source of ROS production mitochondria could be major target of ROS attack. Given that ROS are a highly reactive and short-lived species, their effect should be greatest in an immediate area surrounding the locus of ROS production. It is conceivable that mitochondrial membrane constituents, including the ETC. complexes and phospholipid constituents could be the major target of ROS attack. Alterations in the activity of respiratory chain complexes in mitochondria isolated from ischemic and ischemic/reperfused rat heart have been reported [32, 35, 36, 107].

Several recent publications present evidence that melatonin has significant protective action against the cardiac damage and altered physiology that occur during ischemia/reperfusion injury [108–110]. This protective effect of melatonin has been also demonstrated in ischemia/reperfusion of rat liver [111]. Our studies have demonstrated that melatonin, at pharmacological concentrations, strongly protects against ischemic/reperfusion myocardial damage [35]. This protective effect of melatonin appears to be produced through its action at mitochondrial level. In fact, melatonin treatment of ischemic/reperfused rat heart, significantly lowered the degree of lipid peroxidation, counteracted the reduction in state 3 respiration and the associated decrease in the respiratory control ratio and prevented the loss in complex I and complex III activities in isolated rats heart mitochondria. In addition, melatonin treatment largely prevented the increase in the H2O2 production, the loss in CL content and the increase in its level of peroxidation. The protective effect of melatonin against these mitochondrial bioenergetic alterations was also demonstrated in ‘in vitro’ experiments on isolated rat heart mitochondria. The protection afforded by melatonin against mitochondrial dysfunction that occurs during cardiac ischemia/reperfusion injury was associated with an improvement of postischemic hemodynamic function of the heart as reflected in the greater LVDp and lower LVEDp. The mechanism of protection is likely to be due, at least in part, to the antioxidant efficacy of melatonin preventing CL peroxidation. Together, these data demonstrate that melatonin, at pharmacological concentrations, strongly protects against the alterations to oxidative metabolism, thus limiting cardiac reperfusion injury.

The lipophicity of melatonin allows it to accumulate in the inner mitochondrial membrane, where it scavenges reactive species generated during respiration. Thus, in addition to preventing CL peroxidation, melatonin may also protect directly mitochondrial ETC. complexes from oxidative damage, and this may contribute to protect mitochondrial function. Melatonin has also been shown to increase, in vitro, the activity of the mitochondrial respiratory complexes I and IV [91, 92]. Therefore, the ability of melatonin to directly influence the activity of these respiratory complexes could also contribute to the observed protective effect of this indoleamine against mitochondrial dysfunction associated with heart ischemia/reperfusion.

Cardiolipin, melatonin and mitochondrial permeability transition

Under physiological condition, the mitochondrial inner membrane is impermeable to almost all metabolites and ions. However, under conditions of high matrix Ca2+, especially when associated with enhanced ROS production, high phosphate, and low adenine nucleotide concentrations, an unspecific pore opens that allows passive diffusion of any molecules of <1.5 KDa, thus disrupting the permeability barrier of the inner mitochondrial membrane. This leads to the disruption of ionic homeostasis and uncoupling of oxidative phosphorylation causing irreversible damage to mitochondria resulting in necrotic cell death [112, 113]. The molecular structure of the mitochondrial permeability transition pore (MPTP) remains still uncertain. However, the cyclofillin D, the ANT and the voltage-dependent anion channel (VDAC) appear to be key structural components, while other proteins such as benzodiazepine receptors, exokinase and creatine kinase, Bax and Bcl2 may play a regulatory role [113].

Multiple studies point to a role of the MPTP in the early stages of the apoptotic or necrotic pathway of cell death [114–116]. Release of cytochrome c, as well as other proteins, from the mitochondria to the cytosol, appears to be a central event in the induction of the apoptotic cascade that ultimately leads to the programmed cell death. Cytochrome c, a component of the respiratory chain, is normally bound to the outer surface of the inner mitochondrial membrane primarily to CL molecules [117]. Oxidation of CL promotes the detachment of cytochrome c from mitochondria [118, 119]. It is now accepted that cytochrome c release during apoptosis occurs via a two-step process involving first, the dissociation of the hemoprotein from the outer surface of the inner mitochondrial membrane, followed by permeabilization of the outer mitochondrial membrane and the release of cytochrome c into the extramitochondrial space [41, 114]. CL peroxidation may be involved in the permeabilization of the outer mitochondrial membrane, probably through its association with Bcl2 family proteins such as Bax and Bid [39, 114, 120].

Recently, we reported that oxidized CL, added exogenously to heart mitochondria, in the presence of Ca2+, promotes the mitochondrial permeability transition pore opening and the release of cytochrome c [121]. These effects seem to involve an interaction of these two agents with the ADP/ATP carrier, which is considered a component of the MPTP. The involvement of oxidized CL in MPTP opening is further supported by our recent study showing that oxidation of intramitochondrial CL molecules results in MPTP induction [122]. In fact, peroxidation of intramitochondrial CL molecules after exposure of mitochondria to t-BuOOH, in the presence of low concentrations of Ca2+, results in matrix swelling, ΔΨ collapse, release of preaccumulated Ca2+, and release of cytochrome c. All these events are inhibited by cyclosporine A, indicating that peroxidation of CL molecules, in the presence of Ca2+, induces MPTP opening and cytochrome c release. Melatonin, at micromolar concentration, inhibited the Ca2+/t-BuOOH MPTP induction as shown by its protective effect on matrix swelling, ΔΨ collapse and release of preaccumulated Ca2+. Moreover, melatonin inhibited CL peroxidation in Ca2+/tBuOOH-treated mitochondria. These results indicate that melatonin inhibits MPTP opening and this effect is most likely related to its ability to prevent CL peroxidation. Inhibition of MPTP opening by melatonin has been also reported in other studies [123–125]. In addition, our results demonstrate that the release of cytochrome c from mitochondria, after treatment of these organelles with Ca2+/t-BuOOH, is almost completely prevented by melatonin. This effect of melatonin can be explained on its ability to inhibit CL peroxidation, thereby preventing both cytochrome c detachment from the mitochondrial inner membrane and MPTP induction. Together, our results demonstrate that peroxidation of mitochondrial CL in the presence of Ca2+ induces MPTP opening and cytochrome c release from mitochondria. Melatonin, at micromolar concentrations is able to prevent CL peroxidation in mitochondria and this effect seems to be responsible for the protection afforded by this agent against the Ca2+/peroxidized CL -dependent MPTP opening and mitochondrial cytochrome c release. This effect of melatonin may have important implications in those physiopathological situations characterized by alterations of Ca2+ homeostasis and accumulation of peroxidized CL in mitochondria, such as ischemia/reperfusion, aging and other degenerative diseases.

Melatonin, cardiolipin and MPTP in heart ischemia/reperfusion

Growing evidence is available supporting a crucial role of mitochondrial MPTP in cardyomyocites cell death occurring during ischemia/reperfusion (I/R) [126, 127]. It has been suggested that MPTP remains closed during the ischemic period, because of the lactate-induced acid conditions. At reperfusion, there is an influx of Ca2+ into mitochondria, a burst of ROS production and rapid correction of acidosis. All these factors contribute to increase the probability of MPTP opening in the early minutes of reperfusion, following a prolonged period of ischemia. Identification and characterization of agents and interventions that can protect the heart from the damaging effect of MPTP are of considerable importance in attenuating I/R induced cardiac dysfunction. The use of antioxidants to prevent cardiac I/R injury via MPTP inhibition appears to be a logical measure to improve myocyte survival. It is now known that available antioxidants have not proven to be especially effective against I/R damage. It is possible that most antioxidants are not freely accessible to mitochondria, the main source of ROS production. The search for mitochondrial target antioxidants is now increasing. As mentioned earlier, melatonin is an antioxidant that can easily reach mitochondria where it seems to accumulate in high concentrations.

Very recently, we have demonstrated that melatonin protects against heart I/R injury by inhibiting MPTP opening [22]. Melatonin treatment significantly improves the functional recovery of Langendorff hearts on reperfusion, reduces the infarct size and decreases necrotic damage, as shown by the reduced release of lactate dehydrogenase [22, 128]. All these effects were accompanied by the inhibition of the MPTP opening detected in situ by the mitochondrial release of NAD+. Furthermore, mitochondria isolated from melatonin-reperfused heart were less sensitive than mitochondria from untreated reperfused heart to Ca2+-induced MPTP opening, as assessed by the CRC (calcium retention capacity). CRC is a sensitive and quantitative measure of the ability of mitochondria to open the MPTP in response to accumulation of Ca2+. Together, these results demonstrate that melatonin protects against heart I/R injury by inhibiting MPTP opening.

The possible mechanism involved in the inhibition of MPTP opening during I/R by melatonin treatment was also investigated [22]. Although Ca2+ overload is considered an important factor responsible for MPTP opening during I/R, it is now accepted that additional factors may contribute to the MPTP opening during heart I/R. As described earlier, oxidized CL behaves as an inducer of MPTP in isolated rat heart mitochondria. Thus, it is possible that an increased level of oxidized CL may increase the probability of MPTP opening during I/R. The mitochondrial content of oxidized CL increases upon reperfusion, while melatonin treatment completely counteracts this effect. The fact that melatonin treatment inhibits both MPTP opening and CL peroxidation following I/R suggests a possible link between these two processes. On this basis, it is plausible that an increased level of peroxidized CL, together with Ca2+ overload, synergistically contribute to MPTP opening during reperfusion and that melatonin treatment inhibits MPTP opening by preventing the oxidative damage to CL. The inhibitory effect of melatonin on mitochondrial CL peroxidation during reperfusion can be reasonably explained on the ability of this indoleamine to inhibit the oxidation of linoleic fatty acid constituents of this phospholipid, as demonstrated in a model system in vitro [106].

In addition to its inhibitory effect on MPTP opening, melatonin inhibits also the release of cytochrome c from mitochondria following I/R. This effect of melatonin can be explained on its ability to inhibit the oxidation of CL thereby preventing cytochrome c detachment from mitochondrial membrane, an event that is considered the initial step in the process of cytochrome c release from mitochondria [39–41]. Thus, the inhibition of cytochrome c release by melatonin treatment may contribute, together to the inhibition of MPT opening, to the protective effect exerted by this compound against mitochondrial dysfunction associated with I/R injury. The powerful mitochondrial protection provided by melatonin against I/R injury, reinforces its therapeutic potential to combat a variety of oxidative stress–induced mitochondrial dysfunctions, as well as mitochondrial-mediated apoptosis in various diseases.

Melatonin, cardiolipin and electron transport chain in aging

Aging is a natural, complex and multifactorial biological process associated with impairment of bioenergetic function, increased oxidative stress, attenuated ability to respond to stresses and increased risk of contracting age-associated diseases. According to the free radical theory of aging, ROS, generated as by-products of biological oxidations, cause random and cumulative oxidative damage to macromolecules, leading to cellular dysfunction with age and eventually cell death [129]. Mitochondria seem to be intimately involved in the aging process because these organelles are considered the main intracellular source of ROS, as well as the major target of free radicals’ attack. According to the mitochondrial theory of aging, ROS produced by the mitochondrial respiratory chain attack mitochondrial constituents including proteins, lipids and mitochondrial DNA [130, 131]. Accumulation of mtDNA mutations may lead to impairment of the respiratory chain complexes, leading to increased mitochondrial ROS production and subsequent accumulation of more mitochondrial DNA mutations [132]. This vicious cycle has been proposed to account for the increased oxidative damage during aging, which leads to the progressive decline of cellular and tissue function as a result of insufficient supply of energy and/or increased susceptibility to apoptosis [133, 134]. The age-related increase in oxidative damage to DNA, lipids and proteins has been well documented [135] along with evidences supporting increased mtDNA deletions [136] and mitochondrial dysfunction with aging [137, 138].

Mitochondrial membrane phospholipids play a causal role in aging and longevity by modulating oxidative stress and molecular integrity. Because of their high content of unsaturated fatty acids and to their location in the inner mitochondrial membrane near to the site of ROS production, CL molecules are particularly prone to peroxidative attack by ROS. It is conceivable that CL may represent an important target of ROS attack in aging. Oxidation/depletion of CL with aging, would negatively impact the biochemical function of mitochondrial membranes leading to cellular dysfunction and eventually cell death. The content of mitochondrial CL was found to decrease in heart [68] and brain tissues [69] of aged animals, associated with an increase in the level of oxidized CL.

A widely recognized experimental fact concerning aging and energy transduction is that a decreased electron transport activity is observed in mitochondrial membranes isolated from rats and mice tissues upon aging, although there is little agreement regarding changes in various electron transport complexes activities with age. Of the five respiratory chain complexes, complex I and IV show a selectively reduced enzymatic activity in mitochondria isolated from different tissues of animals upon aging [68, 69, 139, 140]. Attempts to identify some of the mechanisms responsible for these age-related declines in activity indicate that one possible factor responsible for the reduction in complex I and IV activity might be the oxidation/depletion of mitochondrial CL [68, 69]. This assumption is supported by the finding that CL -liposomes, added exogenously to mitochondria from aged rats, almost completely restore the activity of these enzyme complexes to the value of young control animals. This effect of CL could not be replaced by other major mitochondrial phospholipid constituents such as phosphatidylcholine (PC) and phosphatidylethanolamine (PE) nor by peroxidized CL. Altogether, these results clearly indicate that the defect in complex I and IV activities, observed in mitochondrial from aged rats, could be ascribed, at least in part, to oxidative damage to mitochondrial CL, because of ROS attack to its linoleic fatty acid constituents.

Several properties of melatonin indicate that this compound may be beneficial in aging. Serum levels of melatonin significantly decrease in aged animals compared with young animals [141, 142]. In humans, the total antioxidative capacity of serum correlates well with its melatonin levels. Thus, the reduction in melatonin with age may be the factor in the elevated oxidative damage observed in the elderly. Recent studies, using the senescence-accelerated mouse (SAM), investigated the effects of chronic administration of physiological doses of melatonin on mitochondrial oxidative stress and function [143]. The results of this study show an age-dependent oxidative damage in the heart of SAM mice, which was accompanied by a reduction in the electron transport chain complexes activity and in ATP levels. Chronic melatonin administration between 1 and 10 months of age normalized the redox and the bioenergetic status of the mitochondria and increased ATP levels. These results support the beneficial effect of chronic pharmacological intervention with melatonin, which reduces the deteriorative and functional oxidative changes in heart mitochondria with aging [143].

A large body of experimental evidence suggests that mitochondrial decay is a major contributor to brain tissue alterations associated with aging [140]. A potential role of melatonin in mitigation of changes associated with brain aging has been described [144, 145]. In addition, numerous investigations have identified melatonin as a potential mitochondria-targeted protector to defend against various oxidative stress–associated brain diseases. In a recent study, we demonstrated a decline in the complex I activity and in state 3 respiration and an increase in H2O2 production in brain mitochondria isolated from aged rats [69]. The molecular basis of this decline was ascribed to oxidation/depletion of CL. The alterations to mitochondrial bioenergetic parameters associated with rat brain aging were counteracted by long-term melatonin administration. This protective effect of melatonin appears to be because of melatonin’s ability to directly prevent CL oxidation/depletion in mitochondria, as also supported by results of ‘in vitro’ experiments [69].

Functional impairment of mitochondrial complex I has been also associated with a wide spectrum of age-related neurodegenerative disorders, in particular Parkinson’s disease [146, 147]. Moreover, it has been reported that complex I deficiency, which occurs in numerous neurodegenerative situations, sensitizes neurons to the action of death agonists such as Bax, through mitochondrial CL peroxidation [148]. Thus, melatonin treatment, by preventing age-associated complex I deficiency, may improve mitochondrial physiology in brain aging and age-associated brain diseases.

The functional alterations to the mitochondrial respiratory chain complexes, observed in heart I/R and heart and brain tissues of old animals, because of oxidation/depletion of CL molecules, may increase the electron leak from the electron transport chain, generating more O2· and perpetuating a cycle of oxygen radical-induced damage that ultimately leads to mitochondrial dysfunction. Melatonin, by inhibiting CL peroxidation, would prevent respiratory chain dysfunction and subsequent ROS production, thus interrupting this sequence of events (Fig. 1). This would have beneficial effects in mitochondrial physiopathology. Therefore, melatonin administration might represent a valid therapeutic strategy for combating neurodegenerative and cardiovascular disorders associated with heart and brain aging, in which, both mitochondrial respiratory chain deficiency and CL peroxidation could play a critical role.

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Figure 1.  Schematic diagram of the role of ROS and cardiolipin peroxidation in mitochondrial dysfunction associated with heart ischemia/reperfusion and heart and brain aging and possible mechanism of melatonin protection. Mel = melatonin; CL = cardiolipin; CLOOH = peroxidized cardiolipin; ROS = reactive oxygen species.

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Melatonin, cardiolipin and MPTP in aging

The mitochondrial permeability transition may be a factor in cardiac dysfunction associated with aging. Given the association between deficits of mitochondrial function and aging, an important question is whether MPTP becomes more inducible with aging. An increased susceptibility to Ca2+-induced MPTP opening has been shown in mitochondria isolated from different tissues such as liver, brain and heart of old animals [149–153], although the mechanisms underlying this age-related mitochondrial alterations are still not completely elucidated. As mentioned earlier, oxidized CL behaves as an inducer of MPTP in isolated rat heart mitochondria [121]. This effect of oxidized CL on MPTP is also associated with the release of cytochrome c from mitochondria. It is thus conceivable that an increased level of oxidized CL with age could enhance the susceptibility to Ca2+-induced MPTP opening and promote the release of cytochrome c from mitochondria. In addition, melatonin inhibits CL peroxidation in rat heart mitochondria and prevents MPTP and cytochrome c release [122].

Very recently, we found that heart aging is associated with an increased susceptibility to Ca2+-induced permeability transition and to cytochrome c release from mitochondria (G.Petrosillo, N. Moro, V. Paradies, F.M. Ruggiero and G. Paradies, personal observations). These events may be related to the observed increased extent of apoptosis in aged heart [154]. Long-term treatment with melatonin counteracts both these events. This protective effect of melatonin might be explained on the ability by this indoleamine to inhibit the age-related oxidation of CL, thereby preventing both the detachment of cytochrome c from the inner mitochondrial membrane and its release through the MPTP opening. Figure 2 summarizes the processes involved in melatonin’s actions in preventing ROS-mediated, mitochondrial-dependent cellular apoptosis via inhibition of CL peroxidation.

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Figure 2.  Role of ROS and cardiolipin peroxidation on MPTP opening and cytochrome c release from mitochondria and the effects of melatonin. Respiratory chain–mediated ROS production causes cardiolipin peroxidation which, in turn, promotes the detachment of cytochrome c from the inner mitochondrial membrane, the opening of the MPTP and the release of cytochrome c from the mitochondria. Melatonin prevents this cascade of events by inhibiting cardiolipin peroxidation. ETC. = electron transport chain; ROS = reactive oxygen species; cyt. C = cytochrome c; CL = cardiolipin; CLOOH = peroxidized cardiolipin; MPTP = mitochondrial permeability transition pore; Mel = melatonin.

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The fact that heart mitochondria from old rats are more susceptible to Ca2+-induced activation of MPTP and to cytochrome c release might have important implications in necrotic and apoptotic myocyte cell death associated with ischemia/reperfusion injury as well as with other age-related cardiovascular disorders. Pharmacological intervention with melatonin might help to ameliorate these age-related cardiovascular disorders.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Mitochondria and ROS production
  5. Mitochondrial antioxidant systems
  6. Mitochondrial oxidative damage
  7. Cardiolipin and mitochondrial function
  8. Melatonin and mitochondria
  9. Melatonin and lipid peroxidation
  10. Melatonin and cardiolipin in mitochondrial physiopathology
  11. Conclusions
  12. References

A large body of experimental evidence indicates a beneficial effect of melatonin in a number of physiopathological situations that involve mitochondrial dysfunction as a primary cause of disease. Most of the beneficial effects of melatonin may depend on its effect on mitochondrial bioenergetics mediated via different mechanisms, including an antioxidant action and a direct action of this indoleamine on MPTP opening. It is now becoming clear that CL plays a critical role in controlling several processes involved in mitochondrial bioenergetics, in mitochondrial steps of cell death, as well as in mitochondrial membrane stability and dynamics. Many studies have demonstrated mitochondrial dysfunction associated with CL oxidation/depletion in a variety of physiopathological settings, such as heart I/R, aging and age-related disorders. The recent finding that melatonin is able to prevent CL oxidation/depletion, the MPTP opening and the release of cytochrome c in mitochondria, may have important implications in mitochondrial physiopathology. Thus, melatonin administration may represent a valid therapeutic strategy to combat a variety of oxidative stress–induced mitochondrial dysfunction as well as mitochondrial-mediated apoptosis in various diseases.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Mitochondria and ROS production
  5. Mitochondrial antioxidant systems
  6. Mitochondrial oxidative damage
  7. Cardiolipin and mitochondrial function
  8. Melatonin and mitochondria
  9. Melatonin and lipid peroxidation
  10. Melatonin and cardiolipin in mitochondrial physiopathology
  11. Conclusions
  12. References