Overexpression of phospholipid hydroperoxide glutathione peroxidase phgpx in mitochondria of rbl2h3 cells m15 cells prevented the release of cytochrome c cyt. Cardiolipin plays a role in kcninduced necrosis deepdyve. Cardiolipin cl is a unique dimeric phospholipid that exists almost exclusively in the. Cardiolipin roles in mitochondrial recruitment of proteins that mediate fission and fusion. This unique lipid contributes to various mitochondrial functions, including metabolism, mitochondrial membrane fusion andor fission dynamics, and apoptosis. Initiation of apoptotic signal by the peroxidation of. Keywords apoptosis, cardiolipin, mitophagy, oxidation, translocation. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, chromosomal dna fragmentation, and global vague mrna decay.
Dissociation of cytochrome c from the imm, where it is bound to cardiolipin, represents a necessary first step for cytochrome c release. Molecular structural diversity of mitochondrial cardiolipins. Initiation of apoptotic signal by the peroxidation of cardiolipin of mitochondria. Consequently, this opens up a vast number of different theoretically possible molecular lipid species. We address this role of cardiolipin using the multisubunit mitochondrial tim23 protein transport complex as a model system. Cardiolipin cl1 is a key phospholipid in mitochondrial membranes, playing important roles in maintaining the functional integrity and dynamics of mitochondria in animals and yeasts. Cardiolipinmediated mitochondrial dynamics and stress. Cardiolipin and its different properties in mitophagy and apoptosis. Caspase8mediated processing of bid to form tbid is stimulated by cl. Prevention of peroxidation of cardiolipin liposomes by quinol. Cardiolipin cl, a negativelycharged lipid uniquely found in mitochondria and critical for mitochondrial functions, is found primarily in the inner membrane of the mitochondria where it makes up 20% of the total lipids. Role of cardiolipin in mitochondrial signaling pathways. Apoptosis from ancient greek falling off is a form of programmed cell death that occurs in multicellular organisms.
Apr 18, 2019 cardiolipin modulates the production of energy and participates in inflammation, mitophagy, and cellular apoptosis. However, differences in cardiolipin content between the two mitochondrial membranes, as well as. Mitochondrial apoptosis is dispensable for nlrp3 inflammasome. Article information, pdf download for cardiolipin and its different properties in. Cardiolipin acts as a mitochondrial signalling platform to. Apoptosis has been reported to induce changes in the remodelling of. Role of cardiolipin in mitochondrial function and dynamics. In addition to cardiolipin peroxidation, this impedes electron flux and inhibits. Very recent works by the kagan group and others have shown that the protein is primed for this function by gaining peroxidase activity while still bound to the inner membrane surface of. Request pdf role of cardiolipin in mitochondrial diseases and apoptosis apoptosis is a highly programmed cell death strictly connected to the pathogenesis of many human diseases, including. Cardiolipin cl is a mitochondriaspecific phospholipid which is known to be intimately linked with the mitochondrial bioenergetic machinery. Daniel jones,b,c and jianping hua,d,1 a michigan state universitydepartment of energy plant research laboratory, michigan state university, east lansing.
The oxidized cl transfers from the inner membrane to the outer membrane, and then helps to form a. A cardiolipinspecific oxygenase produces cl hydroperoxides which can result in the conformation change of the lipid. Apoptosis or programmed cell death is a key regulator of physiological growth control and regulation of tissue homeostasis. Two chiral carbons and four fatty acyl chains in cl result in a flexible body allowing interactions with respiratory chain complexes and mitochondrial substrate carriers. Inconsistent with the notion that mitochondrial apoptosis is a general nlrp3 stimulus, staurosporineinduced il1b activation occurred independent of nlrp3 14,15 fig 2a. Apoptotic signaling pathways require cl as a binding platform to. Sep 29, 2017 cardiolipin in apoptosis and mitophagy. Cardiolipin specific peroxidase reactions of cytochrome c in mitochondria during irradiationinduced apoptosis. B the role of cl in the processing of procaspase8 is shown. Recent studies have identified the key roles played by mitochondrial lipid species, and lipidderived signaling molecules. Read cardiolipin plays a role in kcninduced necrosis, chemistry and physics of lipids on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips.
Targeting mitochondrial cardiolipin and the cytochrome c. Whether mitophagy or apoptosis is triggered often depends on the dose or the. Prevention of oxidation of cardiolipin in liposomes 1083 biochemistry moscow vol. During apoptosis, cyt c is released from the intermembrane spaces of mitochondria into the cytosol. Apoptosis is executed on two main apoptotic pathways. Cardiolipin remodeling and loss impairs mitochondrial biogenesis and bioenergetics. Here, we have demonstrated the ability of a catalyticallyreactive nanoparticlebased complex of cytochrome c with cardiolipin cytcl to induce the apoptosis and killing of cancer cells in a monolayer cell culture. The mitochondrial cardiolipin remodeling enzyme lysocardiolipin acyltransferase is a novel target in pulmonary fibrosis. At least 15% of mitochondrial cytc is bound to cardiolipin cl, a lipid largely located in the inner mitochondrial membrane 3, 4, 19. Through a combination of magnetic circular dichroism spectroscopy and potentiometric titrations, we show that both the ferric and ferrous forms of the heme group of a cl. Cardiolipin acts as a mitochondrial signalling platform to launch. Apoptosis also plays a key role in embryonic development, the immune response, viral defence and normal tissue homeostasis. Cardiolipin interacts with a number of proteins and enzymes involved in fundamental mitochondrial bioenergetic processes, such as respiratory chain complexes, mitochondrial substrate carriers and is required for their optimal activity.
One of the most important advances in cancer research in. Turnover of nonessential fatty acids in cardiolipin from the rat heart. Role of mitochondrial lipids in guiding fission and fusion. Two chiral carbons and four fatty acyl chains in cl result in a flexible body allowing interactions with. While many studies have focused on cytochrome c release from mitochondria, little attention has been given to the specific interaction between cardiolipin cl and cytochrome c, the breaching of which likely represents a critical event in the initiation of mitochondrially mediated apoptosis. Request pdf cardiolipin and apoptosis cardiolipin cl is recognized to be an essential phospholipid in eukaryotic energy metabolism so that physiological and pathological. Cytochrome c release from rat liver mitochondria is. Jan 22, 2016 during apoptosis, proapoptotic bax and bak trigger mitochondrial outer membrane mom permeabilization by a mechanism that is not yet fully understood. Further, the mitochondrial apoptosis initiator caspase, caspase9, was not required for canonical nlrp3 activation, nor apoptotic stimulus induced il1b secretion fig 2b. Two chiral carbons and four fatty acyl chains in cl result in a flexible body allowing interactions with respiratory.
In vitro studies demonstrated that lycat modulated bleomycininduced cardiolipin remodeling, mitochondrial membrane potential, reactive oxygen species generation, and apoptosis of alveolar epithelial cells, potential mechanisms of lycatmediated lung protection. Cytochrome c is a wellresearched biomolecule, however, over the past decade, research on cytochrome c has shifted, driven by the necessity to understand this proteins role in triggering apoptosis. In this study, we used arabidopsis thaliana to examine the subcellular. Apr 17, 2018 cardiolipins are a unique class of phospholipids in mitochondrial membranes that are crucial for cellular bioenergetics as they stabilize respiratory chain complexes. Cardiolipin is a tetraacyl anionic phospholipid highly conserved in bacteria and mitochondria, it is a dimeric phosphatidic acid with glycerol, and characteristically it contains a central prochiral carbon, two phosphates, and four acyl chains. Kagan, ve, chu, ct, tyurina, yy, cheikhi, a, bayir, h 2014. Role of cardiolipin in mitochondrial diseases and apoptosis. Distribution changes of mitochondrial cardiolipin following apoptotic. Formation of electrophilic oxidation products from. Pathological changes in cl amount or species composition can have deleterious consequences for mitochondrial function and trigger the production of reactive oxygen species. E3 ligase subunit fbxo15 and pink1 kinase regulate. Sorice m, circella a, cristea im, garofalo t, di renzo l, alessandri c, valesini g, esposti md 2004 cardiolipin and its metabolites move from mitochondria to other cellular membranes during death receptormediated apoptosis.
The effect of existing anticancer therapies is based mainly on the stimulation of apoptosis in cancer cells. However, the molecular basis by which this lipid performs this essential cellular role is not well understood. Each apoptosome can recruit seven dimers of caspase. Cardiolipin distribution to the outer mitochondrial membrane would lead to apoptosis of the cells, as evidenced by cytochrome c cyt c release, caspase8 activation, momp induction and nlrp3 inflammasome activation. Mitochondrial phospholipids are involved in several cellular functions, such as cell respiration, apoptosis, and autophagy. Cardiolipin cl, the signature phospholipid of mitochondrial membranes, is crucial for both mitochondrial function and cellular processes outside of the mitochondria. This profile may also partly explain how these respiratory chain proteins complexes i, iii, and iv, and atp synthase embed into the imm and form. We show that lycat expression is significantly altered in peripheral blood mononuclear cells and lung tissues from patients with ipf, and lycat expression in peripheral blood mononuclear cells directly and significantly correlates with pulmonary function. Cardiolipins cl represent unique phospholipids of bacteria and eukaryotic mitochondria with four acyl chains and two phosphate groups that have been implicated in numerous functions from energy metabolism to apoptosis. Cardiolipin cl, the signature phospholipid of mitochondria, is involved in a plethora of cellular processes and is crucial for mitochondrial function and architecture. The determination of cardiolipin or its antibodies is an attractive therapeutic, diagnostic target in rt and kidney diseases. Cardiolipin cl is a phospholipid that is almost exclusively located in the inner mito. Accumulating evidence now suggests that this unique lipid also has active roles in several of the mitochondriadependant steps of apoptosis.
Frontiers role of cardiolipin in mitochondrial signaling. Probing a complex of cytochrome c and cardiolipin by. Restoration of mitochondrial cardiolipin attenuates cardiac. A role for apoptosis in the heart is described during cardiac development, in ischemia, infarction and in the end stage of heart failure bennett, 2002. Hydrophobic interactions between cytochrome c and cardiolipin converts cytochrome c from an electron carrier to a peroxidase. We are using solidstate nmr spectroscopy to study the interactions between mitochondrial protein cytochrome c and membranes containing the mitochondrial lipid cardiolipin 1. In particular, the interest is focused on the role played by cardiolipin, a phospholipid deeply involved in the first steps of the process culminating in cell apoptosis. The importance of cl in cardiovascular health is underscored by the lifethreatening genetic disorder barth syndrome bths, which manifests clinically as cardiomyopathy, skeletal myopathy, neutropenia, and growth retardation. Unlike necrosis, apoptosis produces cell fragments called apoptotic bodies that phagocytic cells are able to engulf and remove before the contents of the cell can spill out onto surrounding cells and cause damage to them. Cardiolipin cl, also known as diphosphatidylglycerol, is an anionic phospholipid predominantly located in the inner mitochondrial membrane imm. However, cl1s role in plants is just beginning to be elucidated. It is unknown why people with severe bacterial infections develop mitochondrial dysfunction with impaired cellular oxygenation.
Oct 18, 20 cardiolipin plays an important role in mitochondrial respiration and cardiolipin peroxidation is associated with age. Oct 01, 2014 read cardiolipin plays a role in kcninduced necrosis, chemistry and physics of lipids on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. Phospholipid acyl chain diversity controls the tissue. Our experiments leverage the unique information that solidstate nmr can provide on the interactions between proteins and lipids 2. Apoptosis is a controlled process of cell death and maintains the homeostasis of cell populations in tissues and occurs as a defense mechanism in immune reactions or in damaged cells.
Our knowledge of the lipid traffic and membrane dynamics that underline this proliferation has remained superficial, but recent papers. We investigated the regulation of tbidinduced cytochrome c release and apoptosis by phospholipid scramblase 3 pls3. Cytochrome c is thought to play a role in apoptosis via the release of apoptotic factors from the mitochondria. Cardiolipin peroxidation could account for induction of the intrinsic apoptotic pathway. Role of reactive oxygen species and cardiolipin in the. Oct 29, 2014 cardiolipin cl is a unique dimeric phospholipid that exists almost exclusively in the inner mitochondrial membrane imm in eukaryotic cells.
A read is counted each time someone views a publication summary such as the title, abstract, and list of authors, clicks on a figure, or views or downloads the fulltext. An international journal on programmed cell death, 12 5 2007. Oct 10, 20 the role of cardiolipin peroxidation in muscle atrophy has not been investigated, but swollen mitochondria lacking cristae membranes were observed in the rat soleus muscle after hindlimb suspension powers et al. Mounting evidence suggests that a decrease in the level of cl affects cytochrome c binding to the inner. Melatonin reduces early changes in intramitochondrial cardiolipin during apoptosis in u937 cell line. Links with this icon indicate that you are leaving the cdc website the centers for disease control and prevention cdc cannot attest to the accuracy of a nonfederal website. Many proteins are known to interact with cl, and several cocrystal structures of proteincl complexes exist. In hl60, about 50% of total cl is distributed in the outer leaflet of mitochondrial.
Mitochondria are essential and dynamic organelles in eukaryotes. The phospholipid cardiolipin cl is an essential constituent of mitochondrial membranes and plays a role in many mitochondrial processes, including respiration and energy conversion. Mitochondria are surrounded by the outer membrane om, which allows selective. Cytcl nanoparticles were prepared by complexing cytc with different. Nioshtic2 publications search 20043906 signaling role of. The role of cardiolipin and mitochondrial damage in kidney.
The phospholipid cardiolipin mediates the functional interactions of proteins that reside within energyconserving biological membranes. Rongrong he, antistress and health research center, pharmacy college, jinan university, guangzhou, 510632, china. As the name suggests, this cell death pathway originates in the mitochondria. The role of lysocardiolipin acyltransferase lycat, a cardiolipin remodeling enzyme, in the development of pulmonary fibrosis is unknown. Nme4nucleoside diphosphate kinase d in cardiolipin.
Cytochrome c release from rat liver mitochondria is compromised by increased saturated cardiolipin species induced by sucrose feeding. Probing a complex of cytochrome c and cardiolipin by magnetic. After primary synthesis, the mature acyl chain composition of cardiolipin is achieved by at least two remodeling mechanisms. Cardiolipin cl is a unique anionic phospholipid specific to the mitochondria. Ultraviolet resonance raman spectroscopy reveals that, when heated at ph 3, a substantial fraction 30% of cytochrome c converts to a. Abstract cardiolipin cl is a unique phospholipid pl found in. In contrast to most other phospholipids, cardiolipins are substituted with four, rather than only two fatty acyl side chains. Cl influences the activity of electron transport chain enzyme complexes as well as members of the bcl2 family. Cardiolipindependent properties of model mitochondrial. Oxidation of cardiolipin cl by its complex with cytochrome c cyt c plays a crucial role in triggering apoptosis. In this work, we describe the collection of the first systematic.
Cardiolipin cl is recognized to be an essential phospholipid in eukaryotic energy metabolism so that physiological and pathological perturbations in its synthetic and catabolic pathways play key roles in maintaining mitochondrial structure and function, and ultimately cell survival. Cardiolipin cl is a unique dimeric phospholipid that exists almost exclusively in the inner mitochondrial membrane imm in eukaryotic cells. Using a cytofluorimetric approach, we studied intramitochondrial cardiolipin cl distribution in hcw2 cells, an apoptosis resistant clone of human hl60 cells. Cardiolipin cl is a unique phospholipid which is localized and synthesized in the inner. Functional role of cardiolipin in mitochondrial bioenergetics.
Cardiolipin, the heart of mitochondrial metabolism. Cell reports article phospholipid acyl chain diversity controls the tissuespeci. Sex differences and gonadal hormone regulation of brain. Role of phospholipid scramblase 3 in the regulation of. Cardiolipin or mtch2 can serve as tbid receptors during apoptosis. A cl is necessary for the recruitment of lc3, which mediates binding of the phagophore membrane. Cardiolipin mediates membrane and channel interactions of. Biochemical events lead to characteristic cell changes and death. Cardiolipinmediated cellular signaling springerlink. Mitochondrial or intrinsic apoptosis plays a critical role in organismal development, and its dysregulation is implicated in diseases ranging from neurodegeneration to cancer. Cardiolipin mediates membrane and channel interactions of the. Role of cardiolipin in mitochondrial signaling pathways ncbi.
Cardiolipin is a unique phospholipid, which is almost exclusively localized in the mitochondrial inner membrane where it is synthesized from phosphatidylglycerol and cytidinediphosphatediacylglycerol. Furthermore, loss of cardiolipin triggers mitochondria permeability transition pore opening and release of cytochrome. Cardiolipinmediated mitochondrial dynamics and stress response in arabidopsisc w ronghui pan,a,b a. The role of cardiolipin in the regulation of mitochondriadependent apoptosis. Cardiolipin is an anionic lipid found in the mitochondrial membranes of eukaryotes ranging from unicellular microorganisms to metazoans. Pdf role of cardiolipin in mitochondrial signaling pathways. When the calcium concentration reaches a toxic level, this causes cell death.
Overexpression of pls3 enhanced, whereas downregulation of pls3 delayed, tnf. Release of cytochrome c from mitochondria is a central event in apoptosis induction and appears to be mediated by ros. Apoptosis is associated with a dramatic modification of cellular membranes. Cardiolipin and its different properties in mitophagy and. Similar nme4supported cl externalization is likely also involved in apoptosis and inflammatory reactions. Formation of electrophilic oxidation products from mitochondrial cardiolipin in vitro and in vivo in the context of apoptosis and atherosclerosis. Cardiolipin interacts with cytochrome c within the mitochondrial inner membrane, and inhibition of cardiolipin synthesis may trigger apoptosis as a result of cytochrome c release and mitochondrial. Sep 29, 2017 the phospholipid cardiolipin cl is an essential constituent of mitochondrial membranes and plays a role in many mitochondrial processes, including respiration and energy conversion. Because apoptosis cannot stop once it has begun, it is a highly regulated process.
513 135 821 495 1443 1016 1095 1398 1060 1249 1525 1291 463 328 1377 386 892 1010 305 1000 899 1523 287 308 532 1044 238 1128 1042 863 190 468 1405 31 939