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PubMed1993

Dynamics in a protein-lipid complex: nuclear magnetic resonance measurements on the headgroup of cardiolipin when bound to cytochrome c.

Deuterium and phosphorus nuclear magnetic resonance (NMR) has been used to investigate the dynamics of slow motional processes induced in bilayer cardiolipin upon binding with cytochrome c. 31P NMR line shapes suggest that protein binding induces less restricted, isotropic-like motions in the lipid phosphates within the ms time scale of this measurement. However, these motions impart rapid transverse relaxation to methylene deuterons adjacent to the phosphate in the lipid headgroup and so did not feature strongly in the NMR line shapes recorded from these nuclei by using the quadrupolar echo. Nonetheless, motional characteristics of the headgroup deuterons were accessible to a dynamic NMR approach using the Carr-Purcell-Meiboom-Gill multiple-pulse experiment. Compared to the well-studied case of deuterons in fatty acyl chains of bilayer phosphatidylcholine, the motions determining the 2H spin transverse relaxation in the headgroup of bilayer cardiolipin were much faster, having a lower limit in the 5-10 kHz range. On binding with cytochrome c, the T2 effecting motions in the cardiolipin headgroup became faster still, with rates comparable to the residual quadrupolar coupling frequency of the headgroup deuterons (approximately 25 kHz) and so coincided with the time scale for recording the quadrupolar echo (approximately 40 microseconds). It is concluded that the headgroup of cardiolipin does not exclusively report localized dynamic information but is particularly sensitive to collective motions occurring throughout the bilayer molecules. Although the rates of collective modes of motion may be dependent on the lipid type in pure lipid bilayers, these low-frequency fluctuations appear to occupy a similar dynamic range in a variety of lipid-protein systems, including the natural membranes.

Animals↗

PubMed1997

Natural hidden antibodies reacting with DNA or cardiolipin bind to thymocytes and evoke their death.

Both free and hidden natural antibodies to DNA or cardiolipin were obtained from immunoglobulins of a normal donor. The free antibodies reacting with DNA or cardiolipin were isolated by means of affinity chromatography. Antibodies occurring in an hidden state were disengaged from the depleted immunoglobulins by ion-exchange chromatography and were then affinity-isolated on DNA or cardiolipin sorbents. We used flow cytometry to study the ability of free and hidden antibodies to bind to rat thymocytes. Simultaneously, plasma membrane integrity was tested by propidium iodide (PI) exclusion. The hidden antibodies reacted with 65.2 +/- 10.9% of the thymocytes and caused a fast plasma membrane disruption. Cells (28.7 +/- 7.1%) were stained with PI after incubation with the hidden antibodies for 1 h. The free antibodies bound to a very small fraction of the thymocytes and did not evoke death as compared to control without antibodies. The possible reason for the observed effects is difference in reactivity of the free and hidden antibodies to phospholipids. While free antibodies reacted preferentially with phosphotidylcholine, hidden antibodies reacted with cardiolipin and phosphotidylserine.

Animals↗

PubMed1998

Peroxidative damage to cardiac mitochondria: cytochrome oxidase and cardiolipin alterations.

Rat heart mitochondrial membranes exposed to the free radicals generating system tert-butylhydroperoxide/Cu2+ undergo lipid peroxidation as evidenced by the accumulation of thyobarbituric acid reactive substances. Mitochondrial lipid peroxidation resulted in a marked loss of both cytochrome c oxidase activity and cardiolipin content. The alterations in the properties of cytochrome c oxidase were confined to a decrease in the maximal activity (Vmax) with no change in the affinity (Km) with respect to the substrate cytochrome c. Various lipid soluble antioxidants could prevent the lipid peroxidation reaction and the associated loss of cytochrome c oxidase activity. External added cardiolipin but no other phospholipids, nor peroxidized cardiolipin was able to prevent the loss of cytochrome oxidase activity induced by lipid peroxidation. These results establish a close correlation between oxidative damage to cardiolipin and alterations in the cytochrome oxidase activity and may prove useful in probing molecular mechanism of free radicals induced peroxidative damage of mitochondria which has been proposed to contribute to aging and to chronic degenerative diseases.

Animals↗

PubMed1986

Antibodies to cardiolipin in young survivors of myocardial infarction: an association with recurrent cardiovascular events.

Antibodies to cardiolipin were measured in 62 survivors of myocardial infarction under age 45 at 3, 12, and 36 months after the acute event. 13 patients (21%) had raised anticardiolipin antibody levels on at least two of the three sampling occasions. Risk-factor profiles and coronary angiographic findings did not differ between the anticardiolipin-positive group and the rest of the patients. No correlation was found between cardiolipin and anti-DNA antibody levels. 8 of the 13 patients with raised anticardiolipin antibody levels experienced additional cardiovascular events during a follow-up of 36-64 months after the first myocardial infarction: cerebral infarction developed in 2, arterial occlusion of the lower limb in 2, new myocardial infarction in 3, pulmonary emboli in 1, and deep-vein thrombosis in 1. These 8 patients had cardiolipin antibody titres of 5 times the mean for voluntary blood donors. Antibodies to cardiolipin are common in young post-infarction patients and should be interpreted as markers of high risk for recurrent cardiovascular events.

Adult↗

PubMed1992

Cytochrome c interactions with cardiolipin in bilayers: a multinuclear magic-angle spinning NMR study.

The influence of cytochrome c binding to cardiolipin bilayers on the motional characteristics of each component has been analyzed by magic-angle spinning (MAS) NMR. Observations were made by NMR of natural abundance 31P, 13C, and 1H nuclei in the lipid as well as sites enriched with 13C in the protein. Analysis of methyl carbons enriched in ([epsilon-13CH3]methionine)cytochrome c at residues 65 and 80 reveal quite different behavior for these sites when the protein was bound at a 1:15 molar ratio with hydrated cardiolipin. Cross-polarization (CP) shows a single broad resonance downfield in the methyl region which corresponds to the spectral characteristics of methionine 65 in the solution protein when subjected to moderate thermal perturbations. These observations suggest that although methionine 65 remains motionally restricted when the protein binds to the lipid bilayers, this residue becomes less shielded and exposed to more chemically distinct environments than in the native state of the protein. In contrast to its behavior in native oxidized protein, the methionine 80 methyl could be detected following direct pi/2 pulse excitation, and this residue is assumed to be released from the axial ligand site on the heme iron to become more exposed and highly mobile in the protein-lipid complex. An analysis of the CP response for natural abundance 13C nuclei in the lipid reveals a general increase in motions with slower rates (tens of kilohertz) on binding with cytochrome c, except for sites within the region of fatty acyl chain unsaturation which appear to be selectively mobilized in the complex with protein. It is concluded that, aside from effects on the unsaturated segments, the bound protein induces new modes of slow motions in the lipid assemblies rather than restricting the overall reorientation freedom of the lipid. The strong paramagnetic effects observed previously on the relaxation of phosphorus in protein-bound lipid [Spooner, P.J.R., & Watts, A. (1991) Biochemistry 30, 3880-3885] were not extended to any carbon and proton sites observable by MAS NMR in the lipid, and this infers a specific interaction of lipid phosphate groups with the heme. However, when protein was bound to cardiolipin mixed at a 1:4 mole ratio with dioleoylphosphatidylcholine in bilayers, no direct interaction with the heme was apparent from the phosphorus NMR relaxation behavior in this component, resolved by MAS. Instead, the spectral anisotropy of cardiolipin phosphorus was determined to be reduced, indicating that, on binding with cytochrome c, the headgroup organization was perturbed in this component.(ABSTRACT TRUNCATED AT 400 WORDS)

Carbon Isotopes↗

PubMed1984

Spin-labeling study of phosphatidylcholine-cardiolipin binary mixtures.

Electron paramagnetic resonance spectra of the spin-label probe 2,2,6,6-tetramethylpiperidinyl-1-oxy have been used to study the phase behavior of binary mixtures of different phosphatidylcholines (dipalmitoyl, distearoyl, and dioleoyl) with cardiolipin, using either calcium-free or calcium-containing cardiolipin (with a calcium:cardiolipin ratio of 1:2) samples. Results show that the nature of the fatty acid chains of the phosphatidylcholines (chain length and unsaturation) may influence the coexistence of different phases as well as does the nature of the cation linked to the cardiolipin.

Animals↗

PubMed2004

Neosynthesis of cardiolipin in Rhodobacter sphaeroides under osmotic stress.

The phospholipid composition of Rhodobacter sphaeroides cells resuspended in various hypertonic solutions has been examined by thin-layer chromatography and ESI mass spectrometry. R. sphaeroides responds to hyperosmotic stress by increasing the amount of cardiolipin in the membranes; this phenomenon occurs in spheroplasts also. Cardiolipin increases quickly and continuously during the time when the cells are resuspended in hypertonic medium. The optimum of stimulation of the neosynthesis of cardiolipin during osmotic stress was found to be at external 1 osm. ESI-MS analyses allowed the identification of two different cardiolipins in R. sphaeroides: the tetravaccenylcardiolipin ([M - H](-), m/z 1456.9) and the trivaccenylmonopalmitoylcardiolipin ([M - H](-), m/z 1430.0).

Cardiolipins↗

PubMed2000

Annexin V binding perturbs the cardiolipin fluidity gradient in isolated mitochondria. Can it affect mitochondrial function?

The phosholipid bilayer fluidity of isolated mitochondria and phospholipid vesicles after calcium-dependent binding of annexin V was studied using EPR spectroscopy. The membranes were probed at different depths by alternatively using cardiolipin, phosphatidylcholine, or phosphatidylethanolamine spin labeled at position C-5 or C-12 or C-16 of the beta acyl chain. Computer-aided spectral titration facilitated observing and quantitating the EPR spectrum from phospholipid spin labels affected by annexin binding, and spectral mobility was calibrated by comparison with standard spectra scanned at various temperatures. In most cases it was found that binding of the protein to the membranes makes the inner bilayer more rigid up to acyl position C-12 than afterward, in agreement with the previously observed effect in SUVs [Megli, F. M., Selvaggi, M., Liemann, S., Quagliariello, E., and Huber, R. (1998) Biochemistry 37, 10540-10546]. Moreover, in isolated mitochondrial membranes, cardiolipin apparently is more readily affected than the other main phospholipids, while in vesicles made from mitochondrial phospholipids, the different species are affected in essentially the same way. This behavior is consistent with the existence of distinct cardiolipin pools in mitochondria, and with the already advanced hypothesis that these domains are the binding site for annexin V to the isolated organelles [Megli, F. M., Selvaggi, M., De Lisi, A., and Quagliariello, E. (1995) Biochim. Biophys. Acta 1236, 273-278]. Keeping in mind the funcional importance of cardiolipin in the mitochondrial membrane, the question is raised as to whether the observed influence of annexin V binding to this phospholipid and its consequent local fluidity alteration might affect the mitochondrial functionality, at least in vitro.

Animals↗

PubMed1999

Enzymatic properties of vesicle-reconstituted human cytochrome P450SCC (CYP11A1) differences in functioning of the mitochondrial electron-transfer chain using human and bovine adrenodoxin and activation by cardiolipin.

The recently reported heterologous expression and purification of both human cytochrome P450SCC and adrenodoxin [Woods, S.T., Sadleir, J., Downs, T., Triantopoulos, T., Haedlam, M.J. & Tuckey, R.C. (1998) Arch. Biochem. Biophys. 353, 109-115] has enabled us to perform studies with the membrane-reconstituted human enzymes to better understand the side-chain cleavage reaction in humans. Human P450SCC was successfully reconstituted into dioleoylphosphatidylcholine vesicles with and without cardiolipin and its enzymatic properties characterized in the membrane-bound state. Enhancement of the P450SCC activity and significant activation by cardiolipin were observed when human adrenodoxin instead of bovine adrenodoxin was used as electron donor. In the absence of cardiolipin, Km for cholesterol was decreased twice in the case of human adrenodoxin indicating enhanced cholesterol binding. On the other hand, in the presence of cardiolipin in the membrane both Km and V for cholesterol were decreased with human adrenodoxin as electron donor. Kinetic analysis of the interaction between human P450SCC and its redox partners provided evidence for enhanced binding of the human electron donor to human P450SCC indicated by both an increased V and decreased Kd for human adrenodoxin compared with the values with bovine adrenodoxin. Because no similar effects were observed in Tween 20 micelles, these results suggest that the phospholipid membrane may play an important role in the interaction of human adrenodoxin with human P450SCC.

Adrenodoxin↗

PubMed2000

A hydrophobic sequence at position 313-316 (Leu-Ala-Phe-Trp) in the fifth domain of apolipoprotein H (beta2-glycoprotein I) is crucial for cardiolipin binding.

Apolipoprotein H (apoH, protein; APOH, gene) binds to negatively charged phospholipids, which triggers the production of a subset of autoantibodies against phospholipid in patients with autoimmune diseases. We have demonstrated that two naturally occurring missense mutations in the fifth domain of apoH, Trp316Ser and Cys306Gly, disrupt the binding of native apoH to phosphatidylserine [Sanghera, D. K., Wagenknecht, D. R., McIntyre, J. A. & Kamboh, M. I. (1997) Hum. Mol. Genet. 6, 311-316]. To confirm whether these are functional mutations, we mutagenized APOH cDNAs and transiently expressed them in COS-1 cells. The cardiolipin ELISA of wild-type and mutant recombinant apoH confirmed that the Gly306 and Ser316 mutations are responsible for abolishing the binding of recombinant apoH to cardiolipin. These mutations, however, had no effect on the levels of expression or secretion of recombinant apoH in transfected COS-1 cells. While the Cys306Gly mutation disrupts a disulfide bond between Cys306 and Cys281, which appears to be critical for clustering positively charged amino acids, the Trp316Ser mutation affects the integrity of an evolutionarily conserved hydrophobic sequence at position 313-316 (Leu-Ala-Phe-Trp), which is hypothesized to interact with anionic phospholipid. To test this hypothesis, we exchanged the remaining three hydrophobic amino acids with neutral amino acids by site-directed mutagenesis (Leu313Gly, Ala314Ser and Phe315Ser). Binding of the Leu313Gly and Phe315Ser mutants to cardiolipin was significantly reduced to 25% and 13%, respectively, of that of the wild-type. On the other hand, the Ala314Ser mutation showed normal cardiolipin binding. Taken together with our previous findings, these results strongly suggest that the configuration of the fifth domain of apoH, as well as the integrity of the highly conserved hydrophobic amino acids at positions 313-316, is essential for the binding of apoH to anionic phospholipid.

Amino Acid Substitution↗

PubMed1996

Regulation of cardiolipin biosynthesis in H9c2 cardiac myoblasts by cytidine 5'-triphosphate.

The regulation of cardiolipin biosynthesis by CTP in H9c2 cardiac myoblasts was investigated. H9c2 cells were incubated in the presence of cyclopentenylcytosine which is converted to cyclopentenylcytosine-triphosphate, a potent and specific inhibitor of CTP synthetase. Incubation of cells for 12 h with cyclopentenylcytosine reduced the cellular pool size of CTP to less than 10% of control cells but did not influence the pool size of other nucleotides. The de novo biosynthesis of phosphatidylcholine from [methyl-3H]choline, phosphatidylethanolamine from [1-3H]ethanolamine, and biosynthesis of all glycerol containing phospholipids from [U-14C]glycerol or [1,3-3H]glycerol were reduced approximately 50% after preincubation of the cells with cyclopentenylcytosine. In contrast, radioactive glycerol accumulated in phosphatidic acid, diacylglycerol, and triacylglycerol in cyclopentenylcytosine-treated cells compared with controls suggesting a re-routing of phospholipid biosynthesis away from CTP utilizing reactions toward neutral lipid synthesis. The de novo biosynthesis of all phospholipids was restored to control levels by addition of cytidine to the medium which elevated CTP levels. Cyclopentenylcytosine did not affect the in vitro enzyme activities involved in cardiolipin biosynthesis in these cells. In addition, the resynthesis of cardiolipin and most phospholipids from [1-14C]linoleic acid was not affected by cyclopentenylcytosine. Our findings indicate that the cellular CTP level may regulate cardiolipin biosynthesis in H9c2 cardiac myoblasts and support the notion that the cellular CTP level may be a universal signal/switch for all phospholipid biosynthesis in eukaryotic cells.

Animals↗

PubMed2003

Only one splice variant of the human TAZ gene encodes a functional protein with a role in cardiolipin metabolism.

Barth syndrome (BTHS) is an X-linked recessive disorder caused by mutations in the TAZ gene and is characterized by cardiomyopathy, short stature, neutropenia, and 3-methylglutaconic aciduria. Recently it was found that BTHS patients exhibit a profound cardiolipin deficiency although the biosynthetic capacity to synthesize this lipid from its precursor phosphatidylglycerol is entirely normal. Like BTHS patients, a Saccharomyces cerevisiae strain, in which the yeast orthologue of the human TAZ gene has been disrupted, exhibits an abnormal cardiolipin profile as determined by tandem mass spectrometry. Additionally, this yeast strain grows poorly on non-fermentable carbon sources. We have used both properties of this yeast disruptant as a read-out system to test the physiological functionality of each of 12 different splice variants that have been reported for the human TAZ gene. Our results demonstrate that only the splice variant lacking exon 5 was able to complement the retarded growth of the yeast disruptant on selective plates and restore the cardiolipin profile to the wild type pattern. We conclude that this splice variant most likely represents the only physiologically important mRNA, at least with regard to cardiolipin metabolism.

Acyltransferases↗

PubMed2004

A novel cardiolipin-remodeling pathway revealed by a gene encoding an endoplasmic reticulum-associated acyl-CoA:lysocardiolipin acyltransferase (ALCAT1) in mouse.

Cardiolipin is a major membrane polyglycerophospholipid that is required for the reconstituted activity of a number of key mitochondrial enzymes involved in energy metabolism. Cardiolipin is subjected to remodeling subsequent to its de novo biosynthesis to attain appropriate acyl composition for its biological functions. Yet, the enzyme(s) involved in the remodeling process have not been identified. We report here the identification and characterization of a murine gene that encodes an acyl-CoA:lysocardiolipin acyltransferase 1 (ALCAT1). Expression of the ALCAT1 cDNA in either insect or mammalian cells led to a significant increase in acyl-CoA:monolysocardiolipin acyltransferase and acyl-CoA: dilysocardiolipin acyltransferase activities that exhibited a dependence upon ALCAT1 enzyme levels. The recombinant ALCAT1 enzyme recognizes both monolysocardiolipin and dilysocardiolipin as substrates with a preference for linoleoyl-CoA and oleoyl-CoA as acyl donors. In contrast, no significant increases in acyltransferase activities by the recombinant ALCAT1 were detected against either glycerol-3-phosphate or a variety of other lysophospholipids as substrates, including lysophosphatidylcholine, lysophosphatidylethanolamine, and lysophosphatidylserine. Immunocytohistochemical analysis showed that the ALCAT1 enzyme is localized in the endoplasmic reticulum, which is supported by a significant ALCAT activity in isolated liver and heart microsomes. Northern blot analysis indicates that the mouse ALCAT1 is widely distributed, with the highest expression in heart and liver. In support of a role for ALCAT1 in maintaining heart function, the ALCAT1 gene is conserved among different species of vertebrates, but not in non-atrium organisms. ALCAT1 represents the first identified cardiolipin-remodeling enzyme from any living organism; its identification implies a novel role for the endoplasmic reticulum in cardiolipin metabolism.

Acyltransferases↗

PubMed2004

Ca2+-induced reactive oxygen species production promotes cytochrome c release from rat liver mitochondria via mitochondrial permeability transition (MPT)-dependent and MPT-independent mechanisms: role of cardiolipin.

Release of cytochrome c from mitochondria is considered a critical, early event in the induction of an apoptosis cascade that ultimately leads to programmed cell death. Mitochondrial Ca(2+) loading is a trigger for the release of cytochrome c, although the molecular mechanism underlying this effect is not fully clarified. This study tested the hypothesis that distinct Ca(2+) thresholds may induce cytochrome c release from rat liver mitochondria by membrane permeability transition (MPT)-dependent and independent mechanisms. The involvement of reactive oxygen species (ROS) and cardiolipin in the Ca(2+)-induced cytochrome c release was also investigated. Cytochrome c was quantitated by a new, very sensitive, and rapid reverse-phase high performance liquid chromatography method with a detection limit of 0.1 pmol/sample. We found that a low extramitochondrial Ca(2+) level (2 microM) promoted the release of approximately 13% of the total alamethicin releasable pool of cytochrome c from mitochondria. This release was not depending of MPT; it was mediated by Ca(2+)-induced ROS production and cardiolipin peroxidation and appears to involve the voltage-dependent anion channel. High extramitochondrial Ca(2+) level (20 microM) promoted approximately 45% of the total releasable pool of cytochrome c. This process was MPT-dependent and was also mediated by ROS and cardiolipin. It is suggested that distinct Ca(2+) levels may determine the mode and the amount of cytochrome c release from rat liver mitochondria. The data may help to clarify the molecular mechanism underlying the Ca(2+)-induced release of cytochrome c from rat liver mitochondria and the role played by ROS and cardiolipin in this process.

Alamethicin↗

PubMed1997

Effect of cardiolipin on functional properties of isolated rat liver mitochondria.

The specific involvement of cardiolipin in modulating and/or controlling the activity of a number of mitochondrial carriers, enzymes and receptors is well documented; however, comparatively less understood is its role for the integrated functions of intact mitochondria. The aim of the present research was to get a better insight into this problem by investigating the effect of in vitro addition of cardiolipin on the properties of isolated liver mitochondria. The results obtained show that cardiolipin induces extensive structural and functional perturbations at the level of the inner mitochondrial membrane. In fact, addition of cardiolipin to intact mitochondria causes a significant increase of proton leak associated with a parallel increase of respiratory rate in State 4. Concomitantly, a slight uncoupling of phosphorylation associated with a moderate increase in ATPase activity is observed. Furthermore, the pore-mediated membrane permeability to calcium is drastically modified, an effect that can be reversed by addition of cyclosporin.

Adenosine Triphosphatases↗

PubMed1990

Cardiolipin molecular species in rat heart mitochondria are sensitive to essential fatty acid-deficient dietary lipids.

Feeding various dietary lipids did not alter the mass of phospholipids in rat heart mitochondria, but the phospholipids' fatty acid compositions changed. Although the compositional changes in mitochondrial phosphatidylcholine and phosphatidylethanolamine were negligible, linoleic acid [cis 18:2(n-6)] of cardiolipin was replaced by other fatty acids from dietary lipids. An analysis of the molecular species showed an even greater extent of change than was observed by fatty acid composition analysis. The quantity of 18:2(n-6)/18:2(n-6) molecular species [18:2(n-6) in C-1 position/18:2(n-6) in C-2 position] in cardiolipin decreased when rats were fed lipids that were depleted of an essential fatty acid but not deficient in essential fatty aids (eicosatrienoic acid did not appear). The decrease in 18:2(n-6)/18:2(n-6) species in cardiolipin was most pronounced in rats fed sardine oil, in which the ratio of (n-3) to (n-6) polyunsaturated fatty acids was 0.2. The O2 consumption rate of rat heart mitochondria decreased as the quantity of 18:2 (n-6)/18:2(n-6) cardiolipin species decreased.

Animals↗

PubMed2003

Decreased complex III activity in mitochondria isolated from rat heart subjected to ischemia and reperfusion: role of reactive oxygen species and cardiolipin.

Reactive oxygen species (ROS) are considered an important factor in ischemia-reperfusion injury to cardiac myocites. We have examined the effects of ischemia (30 min) and ischemia followed by reperfusion (15 min) of rat hearts on the activity of complex III and on the cardiolipin content in isolated mitochondria. Mitochondrial production of H2O2 and lipid peroxidation was also measured. The capacity of mitochondria to produce both H2O2 and lipid peroxidation increased upon reperfusion. The activity of complex III was 22% and 46% lower in ischemic and reperfused rat heart mitochondria, respectively, than that of controls. These changes in complex III activity were associated to parallel changes in state 3 respiration. The mitochondrial content of cardiolipin, which is required for optimal activity of complex III, decreased by 28% and by 50% as a function of ischemia and reperfusion, respectively. The lower complex III activity in mitochondria from reperfused rat hearts could be completely restored to the level of normal hearts by exogenously added cardiolipin. It is proposed that the loss of complex III activity in reperfused rat hearts can be mainly ascribed to a loss of cardiolipin content, due to oxidative attack by oxygen free radicals.

Animals↗

PubMed2006

Protective effect of melatonin against mitochondrial dysfunction associated with cardiac ischemia- reperfusion: role of cardiolipin.

Reactive oxygen species (ROS) are considered an important factor in ischemia/reperfusion injury to cardiac myocytes. Mitochondrial respiration, mainly at the level of complex I and III, is an important source of ROS generation and hence a potential contributor of cardiac reperfusion injury. Appropriate antioxidant strategies could be particularly useful to limit this ROS generation and associated mitochondrial dysfunction. Melatonin has been shown to effectively protect against ischemic-reperfusion myocardial damage. The mechanism by which melatonin exerts this cardioprotective effect is not well established. In the present study we examined the effects of melatonin on various parameters of mitochondrial bioenergetics in a Langerdoff isolated perfused rat heart model. After isolation of mitochondria from control, ischemic-reperfused and melatonin-treated ischemic-reperfused rat heart, various bioenergetic parameters were evaluated such as rates of mitochondrial oxygen consumption, complex I and complex III activity, H2O2 production as well as the degree of lipid peroxidation, cardiolipin content, and cardiolipin oxidation. We found that reperfusion significantly altered all these mitochondrial parameters, while melatonin treatment had strong protective effect attenuating these alterations. This effect appears to be due, at least in part, to the preservation, by ROS attack, of the content and integrity of cardiolipin molecules which play a pivotal role in mitochondrial bioenergetics. Protection of mitochondrial dysfunction was associated with an improvement of post-ischemic hemodynamic function of the heart. Melatonin had also strong protective effect against oxidative alterations to complex I and III as well as to cardiolipin in isolated mitochondria.

Animals↗