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Michael Schlame - One of the best experts on this subject based on the ideXlab platform.
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Metabolism and function of mitochondrial Cardiolipin.
Progress in lipid research, 2014Co-Authors: Mindong Ren, Colin K L Phoon, Michael SchlameAbstract:Since it has been recognized that mitochondria are crucial not only for energy metabolism but also for other cellular functions, there has been a growing interest in Cardiolipin, the specific phospholipid of mitochondrial membranes. Indeed, Cardiolipin is a universal component of mitochondria in all eukaryotes. It has a unique dimeric structure comprised of two phosphatidic acid residues linked by a glycerol bridge, which gives rise to unique physicochemical properties. Cardiolipin plays an important role in the structural organization and the function of mitochondrial membranes. In this article, we review the literature on Cardiolipin biology, focusing on the most important discoveries of the past decade. Specifically, we describe the formation, the migration, and the degradation of Cardiolipin and we discuss how Cardiolipin affects mitochondrial function. We also give an overview of the various phenotypes of Cardiolipin deficiency in different organisms.
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Cardiolipin remodeling and the function of tafazzin
Biochimica et Biophysica Acta, 2013Co-Authors: Michael SchlameAbstract:Abstract Cardiolipin, the specific phospholipid of mitochondria, is involved in the biogenesis, the dynamics, and the supramolecular organization of mitochondrial membranes. Cardiolipin acquires a characteristic composition of fatty acids by post-synthetic remodeling, a process that is crucial for Cardiolipin homeostasis and function. The remodeling of Cardiolipin depends on the activity of tafazzin, a non-specific phospholipid–lysophospholipid transacylase. This review article discusses recent findings that suggest a novel function of tafazzin in mitochondrial membranes. By shuffling fatty acids between molecular species, tafazzin transforms the lipid composition and by doing so supports changes in the membrane conformation, specifically the generation of membrane curvature. Tafazzin activity is critical for the differentiation of cardiomyocytes, in which the characteristic cristae-rich morphology of cardiac mitochondria evolves. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.
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comparison of Cardiolipins from drosophila strains with mutations in putative remodeling enzymes
Chemistry and Physics of Lipids, 2012Co-Authors: Michael Schlame, Mindong Ren, Steven Blais, Irit Edelmannovemsky, Fleurise Montecillo, Colin K L Phoon, Thomas A NeubertAbstract:Abstract Cardiolipin is a dimeric phospholipid with a characteristic acyl composition that is generated by fatty acid remodeling after de novo synthesis. Several enzymes have been proposed to participate in acyl remodeling of Cardiolipin. In order to compare the effect of these enzymes, we determined the pattern of Cardiolipin molecular species in Drosophila strains with specific enzyme deletions, using MALDI-TOF mass spectrometry with internal standards. We established the linear range of the method for Cardiolipin quantification, determined the relative signal intensities of several Cardiolipin standards, and demonstrated satisfying signal-to-noise ratios in Cardiolipin spectra from a single fly. Our data demonstrate changes in the Cardiolipin composition during the Drosophila life cycle. Comparison of Cardiolipin spectra, using vector algebra, showed that inactivation of tafazzin had a large effect on the molecular composition of Cardiolipin, inactivation of calcium-independent phospholipase A2 had a small effect, whereas inactivation of acyl-CoA:lysoCardiolipin-acyltransferase and of the trifunctional enzyme did not affect the Cardiolipin composition.
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Cardiolipin affects the supramolecular organization of atp synthase in mitochondria
Biophysical Journal, 2011Co-Authors: Devrim Acehan, Ashim Malhotra, Yang Xu, David L Stokes, Michael SchlameAbstract:F1F0 ATP synthase forms dimers that tend to assemble into large supramolecular structures. We show that the presence of Cardiolipin is critical for the degree of oligomerization and the degree of order in these ATP synthase assemblies. This conclusion was drawn from the statistical analysis of cryoelectron tomograms of cristae vesicles isolated from Drosophila flight-muscle mitochondria, which are very rich in ATP synthase. Our study included a wild-type control, a Cardiolipin synthase mutant with nearly complete loss of Cardiolipin, and a tafazzin mutant with reduced Cardiolipin levels. In the wild-type, the high-curvature edge of crista vesicles was densely populated with ATP synthase molecules that were typically organized in one or two rows of dimers. In both mutants, the density of ATP synthase was reduced at the high-curvature zone despite unchanged expression levels. Compared to the wild-type, dimer rows were less extended in the mutants and there was more scatter in the orientation of dimers. These data suggest that Cardiolipin promotes the ribbonlike assembly of ATP synthase dimers and thus affects lateral organization and morphology of the crista membrane.
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The role of Cardiolipin in the structural organization of mitochondrial membranes
Biochimica et biophysica acta, 2009Co-Authors: Michael Schlame, Mindong RenAbstract:Considerable progress has recently been made in understanding the role of Cardiolipin in mitochondria. In this brief review, we discuss new data that show how Cardiolipin specifically contributes to the lateral organization of mitochondrial membranes. We argue that the function of Cardiolipin has to be understood in the context of dynamic membrane assembly rather than static membrane structure, and we propose that remodeling of Cardiolipin, i.e. the formation of uniformly substituted molecular species, may reduce the energy barrier of the assembly process.
Francesca Maria Ruggiero - One of the best experts on this subject based on the ideXlab platform.
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functional role of Cardiolipin in mitochondrial bioenergetics
Biochimica et Biophysica Acta, 2014Co-Authors: Giuseppe Paradies, Valeria Paradies, Valentina De Benedictis, Francesca Maria Ruggiero, Giuseppe PetrosilloAbstract:Cardiolipin is a unique phospholipid which is almost exclusively located in the inner mitochondrial membrane where it is biosynthesized. Considerable progress has recently been made in understanding the role of Cardiolipin in mitochondrial function and bioenergetics. This phospholipid is associated with membranes designed to generate an electrochemical gradient that is used to produce ATP, such as bacterial plasma membranes and inner mitochondrial membrane. This ubiquitous and intimate association between Cardiolipin and energy transducing membranes indicates an important role for Cardiolipin in mitochondrial bioenergetic processes. Cardiolipin has been shown to interact with a number of proteins, including the respiratory chain complexes and substrate carrier proteins. Over the past decade, the significance of Cardiolipin in the organization of components of the electron transport chain into higher order assemblies, termed respiratory supercomplexes, has been established. Moreover, Cardiolipin is involved in different stages of the mitochondrial apoptotic process, as well as in mitochondrial membrane stability and dynamics. This review discusses the current understanding of the functional role that Cardiolipin plays in several reactions and processes involved in mitochondrial bioenergetics. This article is part of a Special Issue entitled: Dynamic and ultrastructure of bioenergetic membranes and their components.
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role of Cardiolipin peroxidation and ca2 in mitochondrial dysfunction and disease
Cell Calcium, 2009Co-Authors: Giuseppe Paradies, Valeria Paradies, Giuseppe Petrosillo, Francesca Maria RuggieroAbstract:Cardiolipin is a unique phospholipid which is almost exclusively located at the level of the inner mitochondrial membrane where it is biosynthesized. This phospholipid is known to be intimately involved in several mitochondrial bioenergetic processes. In addition, Cardiolipin also has active roles in several of the mitochondrial-dependent steps of apoptosis and in mitochondrial membrane dynamics. Alterations in Cardiolipin structure, content and acyl chains composition have been associated with mitochondrial dysfunction in multiple tissues in several physiopathological conditions, including ischemia/reperfusion, different thyroid states, diabetes, aging and heart failure. Cardiolipin is particularly susceptible to ROS attack due to its high content of unsaturated fatty acids. Oxidative damage to Cardiolipin would negatively impact the biochemical function of the mitochondrial membranes altering membrane fluidity, ion permeability, structure and function of components of the mitochondrial electron transport chain, resulting in reduced mitochondrial oxidative phosphorylation efficiency and apoptosis. Diseases in which mitochondrial dysfunction has been linked to Cardiolipin peroxidation are described. Ca2+, particularly at high concentrations, appears to have several negative effects on mitochondrial function, some of these effects being linked to CL peroxidation. Cardiolipin peroxidation has been shown to participate, together with Ca2+, in mitochondrial permeability transition. In this review, we provide an overview of the role of CL peroxidation and Ca2+ in mitochondrial dysfunction and disease.
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decrease in mitochondrial complex i activity in ischemic reperfused rat heart involvement of reactive oxygen species and Cardiolipin
Circulation Research, 2004Co-Authors: Giuseppe Paradies, Giuseppe Petrosillo, Marilva Pistolese, Nicola Di Venosa, Antonio Federici, Francesca Maria RuggieroAbstract:Reactive oxygen species (ROS) are considered an important factor in ischemia/reperfusion injury to cardiac myocytes. Mitochondrial respiration is an important source of ROS production and hence a potential contributor to cardiac reperfusion injury. In this study, we have examined the effect of ischemia and ischemia followed by reperfusion of rat hearts on various parameters related to mitochondrial function, such as complex I activity, oxygen consumption, ROS production, and Cardiolipin content. The activity of complex I was reduced by 25% and 48% in mitochondria isolated from ischemic and reperfused rat heart, respectively, compared with the controls. These changes in complex I activity were associated with parallel changes in state 3 respiration. The capacity of mitochondria to produce H2O2 increased on reperfusion. The mitochondrial content of Cardiolipin, which is required for optimal activity of complex I, decreased by 28% and 50% as function of ischemia and reperfusion, respectively. The lower complex I activity in mitochondria from reperfused rat heart could be completely restored to the level of normal heart by exogenous added Cardiolipin. This effect of Cardiolipin could not be replaced by other phospholipids nor by peroxidized Cardiolipin. It is proposed that the defect in complex I activity in ischemic/reperfused rat heart could be ascribed to a ROS-induced Cardiolipin damage. These findings may provide an explanation for some of the factors responsible for myocardial reperfusion injury.
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the effect of reactive oxygen species generated from the mitochondrial electron transport chain on the cytochrome c oxidase activity and on the Cardiolipin content in bovine heart submitochondrial particles
FEBS Letters, 2000Co-Authors: Giuseppe Paradies, Giuseppe Petrosillo, Marilva Pistolese, Francesca Maria RuggieroAbstract:The effect of reactive oxygen species (ROS), produced by the mitochondrial respiratory chain, on the activity of cytochrome c oxidase and on the Cardiolipin content in bovine heart submitochondrial particles (SMP) was studied. ROS were produced by treatment of succinate-respiring SMP with antimycin A. This treatment resulted in a large production of superoxide anion, measured by epinephrine method, which was blocked by superoxide dismutase (SOD). Exposure of SMP to mitochondrial mediated ROS generation, led to a marked loss of cytochrome c oxidase activity and to a parallel loss of Cardiolipin content. Both these effects were completely abolished by SOD+catalase. Added Cardiolipin was able to almost completely restore the ROS-induced loss of cytochrome c oxidase activity. No restoration was obtained with peroxidized Cardiolipin. These results demonstrate that mitochondrial mediated ROS generation affects the activity of cytochrome c oxidase via peroxidation of Cardiolipin which is needed for the optimal functioning of this enzyme complex. These results may prove useful in probing molecular mechanism of ROS-induced peroxidative damage to mitochondria which have been proposed to contribute to aging, ischemia/reperfusion and chronic degenerative diseases.
Giuseppe Paradies - One of the best experts on this subject based on the ideXlab platform.
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functional role of Cardiolipin in mitochondrial bioenergetics
Biochimica et Biophysica Acta, 2014Co-Authors: Giuseppe Paradies, Valeria Paradies, Valentina De Benedictis, Francesca Maria Ruggiero, Giuseppe PetrosilloAbstract:Cardiolipin is a unique phospholipid which is almost exclusively located in the inner mitochondrial membrane where it is biosynthesized. Considerable progress has recently been made in understanding the role of Cardiolipin in mitochondrial function and bioenergetics. This phospholipid is associated with membranes designed to generate an electrochemical gradient that is used to produce ATP, such as bacterial plasma membranes and inner mitochondrial membrane. This ubiquitous and intimate association between Cardiolipin and energy transducing membranes indicates an important role for Cardiolipin in mitochondrial bioenergetic processes. Cardiolipin has been shown to interact with a number of proteins, including the respiratory chain complexes and substrate carrier proteins. Over the past decade, the significance of Cardiolipin in the organization of components of the electron transport chain into higher order assemblies, termed respiratory supercomplexes, has been established. Moreover, Cardiolipin is involved in different stages of the mitochondrial apoptotic process, as well as in mitochondrial membrane stability and dynamics. This review discusses the current understanding of the functional role that Cardiolipin plays in several reactions and processes involved in mitochondrial bioenergetics. This article is part of a Special Issue entitled: Dynamic and ultrastructure of bioenergetic membranes and their components.
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role of Cardiolipin peroxidation and ca2 in mitochondrial dysfunction and disease
Cell Calcium, 2009Co-Authors: Giuseppe Paradies, Valeria Paradies, Giuseppe Petrosillo, Francesca Maria RuggieroAbstract:Cardiolipin is a unique phospholipid which is almost exclusively located at the level of the inner mitochondrial membrane where it is biosynthesized. This phospholipid is known to be intimately involved in several mitochondrial bioenergetic processes. In addition, Cardiolipin also has active roles in several of the mitochondrial-dependent steps of apoptosis and in mitochondrial membrane dynamics. Alterations in Cardiolipin structure, content and acyl chains composition have been associated with mitochondrial dysfunction in multiple tissues in several physiopathological conditions, including ischemia/reperfusion, different thyroid states, diabetes, aging and heart failure. Cardiolipin is particularly susceptible to ROS attack due to its high content of unsaturated fatty acids. Oxidative damage to Cardiolipin would negatively impact the biochemical function of the mitochondrial membranes altering membrane fluidity, ion permeability, structure and function of components of the mitochondrial electron transport chain, resulting in reduced mitochondrial oxidative phosphorylation efficiency and apoptosis. Diseases in which mitochondrial dysfunction has been linked to Cardiolipin peroxidation are described. Ca2+, particularly at high concentrations, appears to have several negative effects on mitochondrial function, some of these effects being linked to CL peroxidation. Cardiolipin peroxidation has been shown to participate, together with Ca2+, in mitochondrial permeability transition. In this review, we provide an overview of the role of CL peroxidation and Ca2+ in mitochondrial dysfunction and disease.
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decrease in mitochondrial complex i activity in ischemic reperfused rat heart involvement of reactive oxygen species and Cardiolipin
Circulation Research, 2004Co-Authors: Giuseppe Paradies, Giuseppe Petrosillo, Marilva Pistolese, Nicola Di Venosa, Antonio Federici, Francesca Maria RuggieroAbstract:Reactive oxygen species (ROS) are considered an important factor in ischemia/reperfusion injury to cardiac myocytes. Mitochondrial respiration is an important source of ROS production and hence a potential contributor to cardiac reperfusion injury. In this study, we have examined the effect of ischemia and ischemia followed by reperfusion of rat hearts on various parameters related to mitochondrial function, such as complex I activity, oxygen consumption, ROS production, and Cardiolipin content. The activity of complex I was reduced by 25% and 48% in mitochondria isolated from ischemic and reperfused rat heart, respectively, compared with the controls. These changes in complex I activity were associated with parallel changes in state 3 respiration. The capacity of mitochondria to produce H2O2 increased on reperfusion. The mitochondrial content of Cardiolipin, which is required for optimal activity of complex I, decreased by 28% and 50% as function of ischemia and reperfusion, respectively. The lower complex I activity in mitochondria from reperfused rat heart could be completely restored to the level of normal heart by exogenous added Cardiolipin. This effect of Cardiolipin could not be replaced by other phospholipids nor by peroxidized Cardiolipin. It is proposed that the defect in complex I activity in ischemic/reperfused rat heart could be ascribed to a ROS-induced Cardiolipin damage. These findings may provide an explanation for some of the factors responsible for myocardial reperfusion injury.
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the effect of reactive oxygen species generated from the mitochondrial electron transport chain on the cytochrome c oxidase activity and on the Cardiolipin content in bovine heart submitochondrial particles
FEBS Letters, 2000Co-Authors: Giuseppe Paradies, Giuseppe Petrosillo, Marilva Pistolese, Francesca Maria RuggieroAbstract:The effect of reactive oxygen species (ROS), produced by the mitochondrial respiratory chain, on the activity of cytochrome c oxidase and on the Cardiolipin content in bovine heart submitochondrial particles (SMP) was studied. ROS were produced by treatment of succinate-respiring SMP with antimycin A. This treatment resulted in a large production of superoxide anion, measured by epinephrine method, which was blocked by superoxide dismutase (SOD). Exposure of SMP to mitochondrial mediated ROS generation, led to a marked loss of cytochrome c oxidase activity and to a parallel loss of Cardiolipin content. Both these effects were completely abolished by SOD+catalase. Added Cardiolipin was able to almost completely restore the ROS-induced loss of cytochrome c oxidase activity. No restoration was obtained with peroxidized Cardiolipin. These results demonstrate that mitochondrial mediated ROS generation affects the activity of cytochrome c oxidase via peroxidation of Cardiolipin which is needed for the optimal functioning of this enzyme complex. These results may prove useful in probing molecular mechanism of ROS-induced peroxidative damage to mitochondria which have been proposed to contribute to aging, ischemia/reperfusion and chronic degenerative diseases.
Valerian E. Kagan - One of the best experts on this subject based on the ideXlab platform.
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surface binding to Cardiolipin nanodomains triggers cytochrome c pro apoptotic peroxidase activity via localized dynamics
Structure, 2019Co-Authors: Abhishek Mandal, Vladimir A. Tyurin, Valerian E. Kagan, Maria Delucia, Jinwoo Ahn, Patrick C A Van Der WelAbstract:The peroxidation of Cardiolipins by reactive oxygen species, which is regulated and enhanced by cytochrome c (cyt c), is a critical signaling event in mitochondrial apoptosis. We probe the molecular underpinnings of this mitochondrial death signal through structural and functional studies of horse heart cyt c binding to mixed-lipid membranes containing Cardiolipin with mono- and polyunsaturated acyl chains. Lipidomics reveal the selective oxidation of polyunsaturated fatty acid (PUFA) Cardiolipin (CL), while multidimensional solid-state NMR probes the structure and dynamics of the membrane and the peripherally bound protein. The hydrophilic milieu at the membrane interface stabilizes a native-like fold, but also leads to localized flexibility at the membrane-interacting protein face. PUFA CL acts as both a preferred substrate and a dynamic regulator by affecting the dynamics of the cyt c N70-I85 Ω loop, which covers the heme cavity.
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lipidomics detection of brain Cardiolipins in plasma is associated with outcome after cardiac arrest
Critical Care Medicine, 2019Co-Authors: Tamil S. Anthonymuthu, Andrew A. Amoscato, Elizabeth M Kenny, Andrew M Lamade, Hitesh Gidwani, Nicholas Krehel, Amalea Misse, Xiaotian Gao, Adam C Straub, Valerian E. KaganAbstract:OBJECTIVES Brain mitochondrial dysfunction limits neurologic recovery after cardiac arrest. Brain polyunsaturated Cardiolipins, mitochondria-unique and functionally essential phospholipids, have unprecedented diversification. Since brain Cardiolipins are not present in plasma normally, we hypothesized their appearance would correlate with brain injury severity early after cardiac arrest and return of spontaneous circulation. DESIGN Observational case-control study. SETTING Two medical centers within one city. PARTICIPANTS (SUBJECTS) We enrolled 41 adult cardiac arrest patients in whom blood could be obtained within 6 hours of resuscitation. Two subjects were excluded following outlier analysis. Ten healthy subjects were controls. Sprague-Dawley rats were used in asphyxial cardiac arrest studies. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS We developed a high-resolution liquid chromatography/mass spectrometry method and determined Cardiolipins speciation in human brain, heart, and plasma within 6 hours of (return of spontaneous circulation) from 39 patients with cardiac arrest, 5 with myocardial infarction, and 10 healthy controls. Cerebral score was derived from brain-specific Cardiolipins identified in plasma of patients with varying neurologic injury and outcome. Using a rat model of cardiac arrest, Cardiolipins were quantified in plasma, brain, and heart. Human brain exhibited a highly diverse Cardiolipinome compared with heart that allowed the identification of brain-specific Cardiolipins. Nine of 26 brain-specific Cardiolipins were detected in plasma and correlated with brain injury. The cerebral score correlated with early neurologic injury and predicted discharge neurologic/functional outcome. Cardiolipin (70:5) emerged as a potential point-of-care marker predicting injury severity and outcome. In rat cardiac arrest, a significant reduction in hippocampal Cardiolipins corresponded to their release from the brain into systemic circulation. Cerebral score was significantly increased in 10 minutes versus 5 minutes no-flow cardiac arrest and naive controls. CONCLUSIONS Brain-specific Cardiolipins accumulate in plasma early after return of spontaneous circulation and proportional to neurologic injury representing a promising novel biomarker.
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magic angle spinning 31p nmr spectroscopy reveals two essentially identical ionization states for the Cardiolipin phosphates in phospholipid liposomes
Biochimica et Biophysica Acta, 2017Co-Authors: Edgar E Kooijman, Hülya Bayır, L A Swim, Z T Graber, Y Y Tyurina, Valerian E. KaganAbstract:Specific membrane lipid composition is crucial for optimized structural and functional organization of biological membranes. Cardiolipin is a unique phospholipid and important component of the inner mitochondrial membrane. It is involved in energy metabolism, inner mitochondrial membrane transport, regulation of multiple metabolic reactions and apoptotic cell death. The physico-chemical properties of Cardiolipin have been studied extensively but despite all these efforts there is still lingering controversy regarding the ionization of the two phosphate groups of Cardiolipin. Results obtained in the 1990s and early 2000s suggested that Cardiolipin has two disparate pKa values where one of the protons was proposed to be stabilized by an intramolecular hydrogen bond. This has led to extensive speculations on the roles of these two putative ionization states of Cardiolipin in mitochondria. More recently the notion of two pKa values has been challenged and rejected by several groups. These studies relied on external measurements of proton adsorption or electrophoretic mobility of membranes but did not take into account the low pH phase behavior and chemical stability of Cardiolipin. Here we used 31P NMR to show that in the physiologically relevant membrane phospholipid environment, Cardiolipin carries two negative charges at physiological pH. We additionally demonstrate the pH dependent phase behavior and chemical stability of Cardiolipin containing membranes.
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characterization of Cardiolipins and their oxidation products by lc ms analysis
Chemistry and Physics of Lipids, 2014Co-Authors: Yulia Y. Tyurina, Vladimir A. Tyurin, Hülya Bayır, Andrew A. Amoscato, Rosario Domingues, Elisabete Maciel, Pedro Domingues, Valerian E. KaganAbstract:Cardiolipins, a class of mitochondria-specific lipid molecules, is one of the most unusual and ancient phospholipids found in essentially all living species. Typical of mammalian cells is the presence of vulnerable to oxidation polyunsaturated fatty acid resides in CL molecules. The overall role and involvement of Cardiolipin oxidation (CLox) products in major intracellular signaling as well as extracellular inflammatory and immune responses have been established. However, identification of individual peroxidized molecular species in the context of their ability to induce specific biological responses has not been yet achieved. This is due, at least in part, to technological difficulties in detection, identification, structural characterization and quantitation of CLox associated with their very low abundance and exquisite diversification. This dictates the need for the development of new methodologies for reliable, sensitive and selective analysis of both CLox. LC-MS-based oxidative lipidomics with high mass accuracy instrumentation as well as new software packages are promising in achieving the goals of expedited and reliable analysis of Cardiolipin oxygenated species in biosamples.
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regulation of enzymatic lipid peroxidation
2013Co-Authors: Ro K. Samhan-arias, Yulia Y. Tyurina, Valerian E. KaganAbstract:susceptible to peroxidative modifications. One of the most contemporary examples includes selective peroxidation of Cardiolipin in mitochondria of cells undergoing apoptosis. Cardiolipin peroxidation products are required for the mitochondrial membrane permeabilization, release of pro-apoptotic factors and completion of the cell death program. Therefore, search for effective inhibitors of Cardiolipin peroxidation is critical to discovery and development of anti-apoptotic antioxidants. Mitochondria contain significant amounts of α-tocopherol, a well known scavenger of reactive free radicals. In the present study, we used an oxidative lipidomics approach to evaluate the effect of α-tocopherol and its homologues with different lengths of the side-chain such as 2,5,7,8,-tetramethyl-2(4-methylpentyl)-6-chromanol and 2,2,5,7,8pentamethyl-6-chromanol, on oxidation of tetralinoleoyl Cardiolipin induced by cytochrome c in the presence of hydrogen peroxide
Giuseppe Petrosillo - One of the best experts on this subject based on the ideXlab platform.
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functional role of Cardiolipin in mitochondrial bioenergetics
Biochimica et Biophysica Acta, 2014Co-Authors: Giuseppe Paradies, Valeria Paradies, Valentina De Benedictis, Francesca Maria Ruggiero, Giuseppe PetrosilloAbstract:Cardiolipin is a unique phospholipid which is almost exclusively located in the inner mitochondrial membrane where it is biosynthesized. Considerable progress has recently been made in understanding the role of Cardiolipin in mitochondrial function and bioenergetics. This phospholipid is associated with membranes designed to generate an electrochemical gradient that is used to produce ATP, such as bacterial plasma membranes and inner mitochondrial membrane. This ubiquitous and intimate association between Cardiolipin and energy transducing membranes indicates an important role for Cardiolipin in mitochondrial bioenergetic processes. Cardiolipin has been shown to interact with a number of proteins, including the respiratory chain complexes and substrate carrier proteins. Over the past decade, the significance of Cardiolipin in the organization of components of the electron transport chain into higher order assemblies, termed respiratory supercomplexes, has been established. Moreover, Cardiolipin is involved in different stages of the mitochondrial apoptotic process, as well as in mitochondrial membrane stability and dynamics. This review discusses the current understanding of the functional role that Cardiolipin plays in several reactions and processes involved in mitochondrial bioenergetics. This article is part of a Special Issue entitled: Dynamic and ultrastructure of bioenergetic membranes and their components.
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role of Cardiolipin peroxidation and ca2 in mitochondrial dysfunction and disease
Cell Calcium, 2009Co-Authors: Giuseppe Paradies, Valeria Paradies, Giuseppe Petrosillo, Francesca Maria RuggieroAbstract:Cardiolipin is a unique phospholipid which is almost exclusively located at the level of the inner mitochondrial membrane where it is biosynthesized. This phospholipid is known to be intimately involved in several mitochondrial bioenergetic processes. In addition, Cardiolipin also has active roles in several of the mitochondrial-dependent steps of apoptosis and in mitochondrial membrane dynamics. Alterations in Cardiolipin structure, content and acyl chains composition have been associated with mitochondrial dysfunction in multiple tissues in several physiopathological conditions, including ischemia/reperfusion, different thyroid states, diabetes, aging and heart failure. Cardiolipin is particularly susceptible to ROS attack due to its high content of unsaturated fatty acids. Oxidative damage to Cardiolipin would negatively impact the biochemical function of the mitochondrial membranes altering membrane fluidity, ion permeability, structure and function of components of the mitochondrial electron transport chain, resulting in reduced mitochondrial oxidative phosphorylation efficiency and apoptosis. Diseases in which mitochondrial dysfunction has been linked to Cardiolipin peroxidation are described. Ca2+, particularly at high concentrations, appears to have several negative effects on mitochondrial function, some of these effects being linked to CL peroxidation. Cardiolipin peroxidation has been shown to participate, together with Ca2+, in mitochondrial permeability transition. In this review, we provide an overview of the role of CL peroxidation and Ca2+ in mitochondrial dysfunction and disease.
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decrease in mitochondrial complex i activity in ischemic reperfused rat heart involvement of reactive oxygen species and Cardiolipin
Circulation Research, 2004Co-Authors: Giuseppe Paradies, Giuseppe Petrosillo, Marilva Pistolese, Nicola Di Venosa, Antonio Federici, Francesca Maria RuggieroAbstract:Reactive oxygen species (ROS) are considered an important factor in ischemia/reperfusion injury to cardiac myocytes. Mitochondrial respiration is an important source of ROS production and hence a potential contributor to cardiac reperfusion injury. In this study, we have examined the effect of ischemia and ischemia followed by reperfusion of rat hearts on various parameters related to mitochondrial function, such as complex I activity, oxygen consumption, ROS production, and Cardiolipin content. The activity of complex I was reduced by 25% and 48% in mitochondria isolated from ischemic and reperfused rat heart, respectively, compared with the controls. These changes in complex I activity were associated with parallel changes in state 3 respiration. The capacity of mitochondria to produce H2O2 increased on reperfusion. The mitochondrial content of Cardiolipin, which is required for optimal activity of complex I, decreased by 28% and 50% as function of ischemia and reperfusion, respectively. The lower complex I activity in mitochondria from reperfused rat heart could be completely restored to the level of normal heart by exogenous added Cardiolipin. This effect of Cardiolipin could not be replaced by other phospholipids nor by peroxidized Cardiolipin. It is proposed that the defect in complex I activity in ischemic/reperfused rat heart could be ascribed to a ROS-induced Cardiolipin damage. These findings may provide an explanation for some of the factors responsible for myocardial reperfusion injury.
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the effect of reactive oxygen species generated from the mitochondrial electron transport chain on the cytochrome c oxidase activity and on the Cardiolipin content in bovine heart submitochondrial particles
FEBS Letters, 2000Co-Authors: Giuseppe Paradies, Giuseppe Petrosillo, Marilva Pistolese, Francesca Maria RuggieroAbstract:The effect of reactive oxygen species (ROS), produced by the mitochondrial respiratory chain, on the activity of cytochrome c oxidase and on the Cardiolipin content in bovine heart submitochondrial particles (SMP) was studied. ROS were produced by treatment of succinate-respiring SMP with antimycin A. This treatment resulted in a large production of superoxide anion, measured by epinephrine method, which was blocked by superoxide dismutase (SOD). Exposure of SMP to mitochondrial mediated ROS generation, led to a marked loss of cytochrome c oxidase activity and to a parallel loss of Cardiolipin content. Both these effects were completely abolished by SOD+catalase. Added Cardiolipin was able to almost completely restore the ROS-induced loss of cytochrome c oxidase activity. No restoration was obtained with peroxidized Cardiolipin. These results demonstrate that mitochondrial mediated ROS generation affects the activity of cytochrome c oxidase via peroxidation of Cardiolipin which is needed for the optimal functioning of this enzyme complex. These results may prove useful in probing molecular mechanism of ROS-induced peroxidative damage to mitochondria which have been proposed to contribute to aging, ischemia/reperfusion and chronic degenerative diseases.