A conserved MADS-box phosphorylation motif regulates differentiation and mitochondrial function in skeletal, cardiac, and smooth muscle cells.

Exposure to metabolic disease during fetal development alters cellular differentiation and perturbs metabolic homeostasis, but the underlying molecular regulators of this phenomenon in muscle cells are not completely understood. To address this, we undertook a computational approach to identify cooperating partners of the myocyte enhancer factor-2 (MEF2) family of transcription factors, known regulators of muscle differentiation and metabolic function. We demonstrate that MEF2 and the serum response factor (SRF) collaboratively regulate the expression of numerous muscle-specific genes, including microRNA-133a (miR-133a). Using tandem mass spectrometry techniques, we identify a conserved phosphorylation motif within the MEF2 and SRF Mcm1 Agamous Deficiens SRF (MADS)-box that regulates miR-133a expression and mitochondrial function in response to a lipotoxic signal. Furthermore, reconstitution of MEF2 function by expression of a neutralizing mutation in this identified phosphorylation motif restores miR-133a expression and mitochondrial membrane potential during lipotoxicity. Mechanistically, we demonstrate that miR-133a regulates mitochondrial function through translational inhibition of a mitophagy and cell death modulating protein, called Nix. Finally, we show that rodents exposed to gestational diabetes during fetal development display muscle diacylglycerol accumulation, concurrent with insulin resistance, reduced miR-133a, and elevated Nix expression, as young adult rats. Given the diverse roles of miR-133a and Nix in regulating mitochondrial function, and proliferation in certain cancers, dysregulation of this genetic pathway may have broad implications involving insulin resistance, cardiovascular disease, and cancer biology.

Essentials of forensic post-mortem MR imaging in adults.

Post-mortem MR (PMMR) imaging is a powerful diagnostic tool with a wide scope in forensic radiology. In the past 20 years, PMMR has been used as both an adjunct and an alternative to autopsy. The role of PMMR in forensic death investigations largely depends on the rules and habits of local jurisdictions, availability of experts, financial resources, and individual case circumstances. PMMR images are affected by post-mortem changes, including position-dependent sedimentation, variable body temperature and decomposition. Investigators must be familiar with the appearance of normal findings on PMMR to distinguish them from disease or injury. Coronal whole-body images provide a comprehensive overview. Notably, short tau inversion-recovery (STIR) images enable investigators to screen for pathological fluid accumulation, to which we refer as "forensic sentinel sign". If scan time is short, subsequent PMMR imaging may be focussed on regions with a positive forensic sentinel sign. PMMR offers excellent anatomical detail and is especially useful to visualize pathologies of the brain, heart, subcutaneous fat tissue and abdominal organs. PMMR may also be used to document skeletal injury. Cardiovascular imaging is a core area of PMMR imaging and growing evidence indicates that PMMR is able to detect ischaemic injury at an earlier stage than traditional autopsy and routine histology. The aim of this review is to present an overview of normal findings on forensic PMMR, provide general advice on the application of PMMR and summarise the current literature on PMMR imaging of the head and neck, cardiovascular system, abdomen and musculoskeletal system.

Placement of coiled catheters into the paravertebral space.

There are conflicting results with regard to the use of catheter-based techniques for continuous paravertebral block. Local anaesthetic spread within the paravertebral space is limited and the clinical effect is often variable. Discrepancies between needle tip position and final catheter position can also be problematic. The aim of this proof-of-concept study was to assess the reliability of placing a newly developed coiled catheter in human cadavers. Sixty Tuohy needles and coiled catheters were placed under ultrasound guidance, three on each side of the thoracic vertebral column in 10 human cadavers. Computed tomography was used to assess needle tip and catheter tip locations. No catheter was misplaced into the epidural, pleural or prevertebral spaces. The mean (SD) distance between catheter tips and needle tips was 8.2 (4.9) mm. The median (IQR [range]) caudo-cephalad spread of contrast dye injectate through a subset of 20 catheters was 4 (4-5[3-8]) thoracic segments. All catheters were removed without incident. Precise paravertebral catheter placement can be achieved using ultrasound-guided placement of a coiled catheter.

Differentiation of ante-mortem and post-mortem fractures with MRI: a case report.

We describe a case of a fatal speed flying accident in which the victim was electrocuted, burned and fell from a great height. Post-mortem imaging revealed acute appearing fractures on CT, without bone marrow oedema on MRI. Based on the known clinical imaging findings of bone marrow oedema in acute fractures, we concluded that the speed flyer died from electrocution rather than the fall and that the fractures occurred post-mortem. Radiological imaging augmented the reconstruction of the peri-mortem events. Further research is needed to assess whether bone marrow oedema in acute fractures is a reliable vital sign.

Modulation of cytosolic phospholipase A(2) by PPAR activators in human preadipocytes.

Cytosolic phospholipase A(2) (cPLA(2)) is responsible for the release of arachidonic acid, a precursor for eicosanoid biosynthesis, from cellular phospholipids. The objective of this study is to examine the regulation of cPLA(2) by peroxisome proliferator-activated receptor (PPAR) activators in preadipocyte SW872 (SW) cells. PPAR belong to the superfamily of nuclear hormone receptors that heterodimerize with the retinoid X receptor. In this study, the presence of both PPARalpha and PPARgamma was confirmed in SW cells by positive identification of their mRNA in the cellular homogenate. Clofibrate, a PPARalpha activator, caused an enhancement of ionophore A-23187-induced arachidonate release in SW cells. This increase resulted from an enhancement of cPLA(2) activity, which was caused by an increase in enzyme protein. Clofibrate at lower concentrations (10-200 microM) produced increases in the mRNA levels of cPLA(2) in a dose-response manner. At higher concentrations (>400 microM), clofibrate treatment resulted in the attenuation of the cPLA(2) mRNA level and protein expression. We postulate that clofibrate, acting through the PPARalpha, caused an induction in the transcription of cPLA(2) gene, which led to an increase in the cPLA(2) protein. The observed increase in arachidonate release in SW cells appeared to be a direct result of the enhanced cPLA(2) activity.

Perturbation of rat renal tubule transport of the organic cation amantadine in recent onset streptozotocin-induced diabetes and in uninephrectomy.

The effects of early-stage diabetes mellitus and uninephrectomy on the renal tubule transport of amantadine were investigated. Kidney tubules were isolated from streptozotocin-induced diabetic (+/- insulin treatment) uninephrectomized, and control male Sprague-Dawley rats. There were no differences in the Km of amantadine uptake in renal proximal and distal tubules for the imposed treatments compared with control values. Vmax for amantadine uptake in the proximal tubules of diabetic and uninephrectomized rats was higher than the respective control (P < 0.05). Vmax for insulin-treated diabetic rats was similar to control values but was lower than that for untreated diabetic rats (P < 0.05). Vmax for distal tubule uptake was not altered by any treatment. Structure-activity studies demonstrated that bicarbonate-dependent amantadine uptake was inhibited by glycolate and lactate, but not by propionate or alpha-, beta-, or gamma-hydroxybutyrate. Early stage streptozotocin-induced diabetes mellitus and uninephrectomy induced changes in the kidney that resulted in a similar selective increase in proximal tubule amantadine uptake. These data represent the first description that experimentally induced diabetes mellitus and uninephrectomy modulate the function of the renal tubule organic cation (amantadine) transport system. Both interventions represent potential models in which phenotypic modulation of the renal elimination of organic cationic drugs may be achieved and studied.

Incorporation of fatty acids into phosphatidylcholine is reduced during storage of human erythrocytes: evidence for distinct lysophosphatidylcholine acyltransferases.

The incorporation of [1-14C]palmitic or [1-14C]oleic acid into phosphatidylcholine and the effect on blood group antigen expression were examined in human erythrocytes stored at 4 degrees C for 0-3 weeks. Blood drawn into EDTA was obtained by venepuncture from healthy volunteers. A 50% suspension of washed erythrocytes was incubated in buffer containing [1-14C]fatty acid for up to 60 min at 37 degrees C with moderate shaking. Phosphatidylcholine was extracted and analyzed for uptake of radiolabelled fatty acid and phospholipid phosphorus content. Incorporation of [1-14C]palmitic or [1-14C]oleic acid into phosphatidylcholine was reduced during storage. The mechanism for the reduction in radiolabelled fatty acid incorporation into phosphatidylcholine was a 64% (p < 0.05) reduction in membrane phospholipase A2 activity. Although human erythrocyte membranes isolated from freshly drawn blood are capable of reacylating lysophosphatidylcholine to phosphatidylcholine, with storage, a markedly different substrate preference between palmitoyl-Coenzyme A and oleoyl-Coenzyme A was observed. Lysophosphatidylcholine acyltransferase activity assayed with oleoyl-Coenzyme A was unaltered with storage. In contrast, lysophosphatidylcholine acyltransferase activity assayed with palmitoyl-Coenzyme A was elevated 5.5-fold (p < 0.05). Despite these changes, storage of erythrocytes for up to 3 weeks did not result in altered expression of the various blood group antigens investigated. We conclude that the incorporation of palmitate and oleate into phosphatidylcholine is dramatically reduced during storage of human erythrocytes. The observed differential in vitro substrate utilization suggests that distinct acyltransferases are involved in the acylation of lysophosphatidylcholine to phosphatidylcholine in human erythrocytes.

Differential effects of chloroquine on cardiolipin biosynthesis in hepatocytes and H9c2 cardiac cells.

Chloroquine is a potent lysomotropic therapeutic agent used in the treatment of malaria. The mechanism of the chloroquine-mediated modulation of new cardiolipin biosynthesis in isolated rat liver hepatocytes and H9c2 cardiac myoblast cells was addressed in this study. Hepatocytes or H9c2 cells were incubated with [1,3-(3)H]glycerol in the absence or presence of chloroquine and cardiolipin biosynthesis was examined. The presence of chloroquine in the incubation medium of hepatocytes resulted in a rapid accumulation of radioactivity in cardiolipin indicating an elevated de novo biosynthesis. In contrast, chloroquine caused a reduction in radioactivity incorporated into cardiolipin in H9c2 cells. The presence of brefeldin A, colchicine or 3-methyladenine did not effect radioactivity incorporated into cardiolipin nor the chloroquine-mediated stimulation of cardiolipin biosynthesis in hepatocytes indicating that vesicular transport, cytoskeletal elements or increased autophagy were not involved in de novo cardiolipin biosynthesis induced by chloroquine. The addition of chloroquine to isolated rat liver membrane fractions did not affect the activity of the enzymes of de novo cardiolipin biosynthesis but resulted in an inhibition of mitochondrial cytidine-5'-diphosphate-1,2-diacyl-sn-glycerol hydrolase activity. The mechanism for the reduction in cardiolipin biosynthesis in H9c2 cells was a chloroquine-mediated inhibition of glycerol uptake and this did not involve impairment of lysosomal function. The kinetics of the chloroquine-mediated inhibition of glycerol uptake indicated the presence of a glycerol transporter in H9c2 cells. The results of this study clearly indicate that chloroquine has markedly different effects on glycerol uptake and cardiolipin biosynthesis in hepatocytes and H9c2 cardiac cells.

The effect of fenofibrate treatment on endothelium-dependent relaxation induced by oxidative modified low density lipoprotein from hyperlipidemic patients.

The objective of the research project was to investigate whether fenofibrate treatment may alter the biochemical content of the oxidized LDL and consequently its ability to impair the endothelium-dependent relaxation in hyperlipidemic patients. We hypothesized that fenofibrate treatment of hyperlipidemic patients may attenuate the ability of their oxidized LDL to impair the endothelium-dependent relaxation of the blood vessels as a consequence of fenofibrate-induced changes to the content and composition of lysoPC in the LDL molecule. Hyperlipidemic patients (Type IIb and Type IV) were recruited from the Lipid Clinic, HSC, Winnipeg, Canada, for this study. A blood sample was taken immediately after the recruitment, a second sample was taken after 6 weeks of dietary treatment, and a third sample was taken after 8 weeks of fenofibrate treatment. LDL was isolated from the plasma and oxidized by copper sulfate. Fenofibrate was shown to be highly effect in the reduction of total cholesterol, LDL cholesterol and triglycerides in these patients. Fenofibrate treatment also caused the attenuation of impairment of endothelium-dependent relaxation by the oxidized LDL from these patients. A slight reduction of lysophosphatidylcholine level was also found in the oxidized LDL of the fenofibrate treated patients, relative to LDL isolated after dietary treatment. In addition there were no changes in the fatty acid levels of the lysophosphatidylcholine isolated from LDL. Taken together, our results suggest that while the reduced lysophosphatidylcholine levels may contribute to the attenuated impairment of the endothelium-dependent relaxation of the aortic ring, other unidentified factors impacted by fenofibrate are likely to contribute to the attenuated effects.

Lysophosphatidylethanolamine acyltransferase activity is elevated during cardiac cell differentiation.

We examined if elevation in lysophosphatidylethanolamine acyltransferase activity was associated with elevation in phosphatidylethanolamine content during differentiation of P19 teratocarcinoma cells into cardiac myocytes. P19 cells were induced to undergo differentiation into cardiac myocytes by the addition of 1% dimethylsulfoxide to the medium. Immunofluorescence microscopy revealed the presence of striated myosin at 8 days post-dimethylsulfoxide addition confirming differentiation into cardiac cells. The content of phosphatidylethanolamine was increased 2.1-fold (P<0.05) in differentiated cells compared to undifferentiated cells, whereas the content of phosphatidylcholine was reduced 29% (P<0.05). There were no alterations in the pool sizes of other phospholipids, including cardiolipin. The relative abundance of fatty acids in phospholipids of P19 cells was 18:1 > 18:0 > 16:1 = 18:2 > 16:0 = 14:0 > 20:4 and differentiation did not affect the relative amounts of these fatty acids within individual phospholipids. When cells were incubated with [1,3-(3)H]glycerol, radioactivity incorporated into phosphatidylethanolamine was elevated 5.8-fold, whereas radioactivity incorporated into phosphatidylcholine was unaltered. Ethanolaminephosphotransferase, cholinephosphotransferase and membrane CTP:phosphocholine cytidylyltransferase activities were elevated in differentiated cells compared to undifferentiated cells, whereas membrane and cytosolic phospholipase A2 activities were unaltered. Lysophosphatidylethanolamine acyltransferase activities were elevated 2.4-fold (P<0.05). Lysophosphatidylcholine acyltransferase, monolysocardiolipin acyltransferase, acyl-Coenzyme A synthetase and acyl-Coenzyme A hydrolase activities were unaltered in differentiated cells compared to undifferentiated cells. We postulate that during cardiac cell differentiation, the observed elevation in lysophosphatidylethanolamine acyltransferase activity accompanies the elevation in phosphatidylethanolamine mass, possibly to maintain the fatty acyl composition of this phospholipid within the membrane.

Elevation in phosphatidylethanolamine is an early but not essential event for cardiac cell differentiation.

The biosynthesis of phosphatidylethanolamine was examined during differentiation of P19 teratocarcinoma cells into cardiac myocytes. P19 cells were induced to undergo differentiation into cardiac myocytes by the addition of dimethyl sulfoxide to the medium. Immunofluorescence labeling confirmed the expression of striated myosin 10 days postinduction of differentiation. The content of phosphatidylethanolamine increased significantly within the first 2 days of differentiation. [1,3-(3)H]Glycerol incorporation into phosphatidylethanolamine was increased 7.2-fold during differentiation, indicating an elevation in de novo synthesis from 1, 2-diacyl-sn-glycerol. The mechanism for the increase in phosphatidylethanolamine levels during cardiac cell differentiation was a 2.8-fold increase in the activity of ethanolaminephosphotransferase, the 1,2-diacyl-sn-glycerol utilizing reaction of the cytidine 5'-diphosphate-ethanolamine pathway of phosphatidylethanolamine biosynthesis. Incubation of P19 cells with the phosphatidylethanolamine biosynthesis inhibitor 8-(4-chlorophenylthio)-cAMP inhibited the differentiation-induced elevation in phosphatidylethanolamine levels but did not affect the expression of striated myosin. The results suggest that elevation in phosphatidylethanolamine is an early event of P19 cell differentiation into cardiac myocytes, but is not essential for differentiation to proceed.

Thyroxine regulation of monolysocardiolipin acyltransferase activity in rat heart.

Treatment of rats with thyroxine has been shown to elevate the biosynthesis and content of cardiolipin in the heart [Cao, Cheng, Angel and Hatch (1995) Biochim. Biophys. Acta 1256, 241-244]. Treatment with thyroxine resulted in a 1.8-fold increase (P<0.025) in [1-(14)C]linoleate and a 1.7-fold increase (P<0.025) in [1-(14)C]oleate incorporated into cardiolipin in perfused hearts, compared with controls. The mechanism for the elevation in incorporation of unsaturated fatty acids into cardiolipin was a 1. 6-fold (P<0.025) increase in mitochondrial monolysocardiolipin acyltransferase activity. The results demonstrate that the acylation of cardiac monolysocardiolipin is regulated by thyroid hormone. Thus an elevation in cardiolipin biosynthesis is accompanied by an elevation in monolysocardiolipin acyltransferase activity to maintain the appropriate molecular species composition of cardiolipin in the cardiac mitochondrial membrane. We postulate that monolysocardiolipin acyltransferase might be a rate-limiting enzyme for the molecular remodelling of cardiolipin in the heart.

Acylation of monolysocardiolipin in rat heart.

Cardiolipin is a major mitochondrial membrane glycerophospholipid in the mammalian heart. In this study, the ability of the isolated intact rat heart to remodel cardiolipin and the mitochondrial enzyme activities that reacylate monolysocardiolipin to cardiolipin in vitro were characterized. Adult rat heart cardiolipin was found to contain primarily linoleic and oleic acids. Perfusion of the isolated intact rat heart in the Langendorff mode with various radioactive fatty acids, followed by analysis of radioactivity incorporated into cardiolipin and its immediate precursor phosphatidylglycerol, indicated that unsaturated fatty acids entered into cardiolipin mainly by deacylation followed by reacylation. The in vitro mitochondrial acylation of monolysocardiolipin to cardiolipin was coenzyme A-dependent with a pH optimum in the alkaline range. Significant activity was also present at physiological pH. With oleoyl-coenzyme A as substrate, the apparent K(m) for oleoyl-coenzyme A and monolysocardiolipin were 12.5 microm and 138.9 microm, respectively. With linoleoyl-coenzyme A as substrate, the apparent K(m) for linoleoyl-coenzyme A and monolysocardiolipin were 6.7 microm and 59.9 microm, respectively. Pre-incubation at 50 degrees C resulted in different profiles of enzyme inactivation for the two activities. Both activities were affected similarly by phospholipids, triacsin C, and various lipid binding proteins but were affected differently by various detergents and myristoyl-coenzyme A. [(3)H]cardiolipin was not formed from monolyso[(3)H]cardiolipin in the absence of acyl-coenzyme A. Monolysocardiolipin acyltransferase activities were observed in mitochondria prepared from various other rat tissues. In summary, the data suggest that the isolated intact rat heart has the ability to rapidly remodel cardiolipin and that rat heart mitochondria contain coenzyme A-dependent acyltransferase(s) for the acylation of monolysocardiolipin to cardiolipin. A simple and reproducible in vitro assay for the determination of acyl-coenzyme A- dependent monolysocardiolipin acyltransferase activity in mammalian tissues with exogenous monolysocardiolipin substrate is also presented.

The subcellular distribution of protein kinase Calpha, -epsilon, and -zeta isoforms during cardiac cell differentiation.

There is little information on the molecular events that control the subcellular distribution of protein kinase C during cardiac cell differentiation. We examined protein kinase C activity and the subcellular distribution of representatives of the "classical," "novel," and "atypical" protein kinase C's in P19 murine teratoma cells induced to undergo differentiation into cardiac myocytes by the addition of dimethylsulfoxide to the medium (Grepin et al., Development 124, 2387-2395, 1997). Differentiation was assessed by the presence of striated myosin, a morphological marker for cardiac cells. Addition of dimethyl sulfoxide to the medium resulted in the appearance of striated myosin by 10 days postincubation. Immunolocalization and Western blot studies revealed that a significant proportion of protein kinase Calpha, -epsilon, and -zeta were associated with the particulate fraction in P19 cells prior to differentiation. Differentiation into cardiac cells resulted in a translocation of protein kinase C activity from the particulate fraction to cytosol and localization of most of protein kinase Calpha, -epsilon, and -zeta to the cytoplasmic compartment. The total cellular protein kinase C activity was unaltered during differentiation. The translocation of protein kinase C activity during differentiation of P19 cells into cardiac myocytes was associated with a decrease in the levels of cellular 1, 2-diacyl-sn-glycerol. The cellular levels of phosphatidylserine and phosphatidylinositol did not change during differentiation. Addition of 1,2-dioctanoyl-sn-glycerol, a cell-permeant 1, 2-diacyl-sn-glycerol analog, reversed the differentiation-induced switch in the relative distribution of protein kinase C activity and dramatically increased the association of protein kinase Calpha with the particulate fraction. Addition of 1,2-dioctanoyl-sn-glycerol did not reverse the pattern of distribution for protein kinase Cepsilon or -zeta. The results indicate that protein kinase C activity and protein kinase Calpha, -epsilon and -zeta isoforms are redistributed from the particulate to the cytosolic fraction during differentiation of P19 cells into cardiomyocytes. The mechanism for the redistribution of protein kinase Calpha may be related to the reduction in the cellular 1,2-diacyl-sn-glycerol levels that accompany differentiation.

N-Acetylsphingosine stimulates phosphatidylglycerolphosphate synthase activity in H9c2 cardiac cells.

Cardiolipin and phosphatidylglycerol biosynthesis were examined in H9c2 cells incubated with short-chain ceramides. Incubation of cells with N-acetylsphingosine or N-hexanoylsphingosine stimulated [1, 3-3H]glycerol incorporation into phosphatidylglycerol and cardiolipin, with N-acetylsphingosine having the greater effect. The mechanism for the ceramide-mediated stimulation of de novo phosphatidylglycerol and cardiolipin biosynthesis appeared to be an increase in the activity of phosphatidylglycerolphosphate synthase, the committed step of phosphatidylglycerol and cardiolipin biosynthesis. The presence of the potent protein phosphatase inhibitors calyculin A or okadaic acid attenuated the N-acetylsphingosine-mediated stimulation of phosphatidylglycerolphosphate synthase activity and of phosphatidylglycerol and cardiolipin biosynthesis, indicating the involvement of a ceramide-activated protein phosphatase(s). The presence of 8-(4-chlorophenylthio)-cAMP (CPT-cAMP) stimulated enzyme activity and [1,3-3H]glycerol incorporation into phosphatidylglycerol and cardiolipin. The effects of CPT-cAMP and N-acetylsphingosine on phosphatidylglycerol and cardiolipin biosynthesis and on phosphatidylglycerolphosphate synthase activity were additive. Phosphatidylglycerol biosynthesis from sn-[14C]glycerol 3-phosphate in permeabilized H9c2 cells was stimulated by preincubation with N-acetylsphingosine, and this was attenuated by okadaic acid. N-Acetylsphingosine treatment of cells elevated mitochondrial phospholipase A2 activity. Since the pool sizes of phosphatidylglycerol and cardiolipin were unaltered in these cells, the observed increase in phosphatidylglycerolphosphate synthase activity may be a compensatory mechanism for the N-acetylsphingosine-mediated elevation of mitochondrial phospholipase A2 activity. Finally, addition of tumour necrosis factor alpha to H9c2 cells resulted in an elevation of both phosphatidylglycerolphosphate synthase and phospholipase A2 activities. The results suggest that phosphatidylglycerol and cardiolipin metabolism in H9c2 cells may be regulated by intracellular ceramide signalling.

Cardiolipin: biosynthesis, remodeling and trafficking in the heart and mammalian cells (Review).

Cardiolipin is the principal polyglycerophospholipid found in the heart and most mammalian tissues. This phospholipid is the only phospholipid localized exclusively to the mitochondria of mammalian cells. Cardiolipin appears to be involved, either directly or indirectly, in the modulation of a number of cellular processes including the activation of mitochondrial enzymes and hence production of energy by oxidative phosphorylation. The regulatory properties which govern cardiolipin biosynthesis, its remodeling and trafficking are beginning to emerge. Studies in the isolated perfused rat heart and H9c2 cardiac myoblast cells have indicated that the rate-limiting step of cardiolipin biosynthesis, via the cytidine-5'-diphosphate-1,2-diacyl-sn-glycerol pathway, is the conversion of phosphatidic acid and cytidine-5'-triphosphate to cytidine-5'-diphosphate-1,2-diacyl-sn-glycerol. The cellular level of cytidine-5'-triphosphate appears to control the production of cardiolipin in H9c2 cells. The activities of the other enzymes of the cytidine-5'-diphosphate-1,2-diacyl-sn-glycerol pathway of cardiolipin biosynthesis in the heart may be modulated by thyroid hormone and unsaturated fatty acids. In addition, extra-mitochondrial cytidine-5'-diphosphate-1,2-diacyl-sn-glycerol and phosphatidylglycerol may be utilized for cardiolipin biosynthesis in the heart and permeabilized cells. Cardiolipin may be readily hydrolyzed by phospholipases and may be remodeled by a deacylation-reacylation pathway. Studies with a Chinese hamster lung fibroblast cell line CCL16-B2 have indicated that the remodeling of cardiolipin is markedly altered in the mitochondria of these cells and that this alteration in remodeling may be one of the underlying mechanisms for the mutation in oxidative energy production in these cells. Host cell cardiolipin may be trafficked from the mitochondria to an intracellular bacterial parasite Chlamydia trachomatis. The purpose of this review is to briefly discuss some of the more recent findings in cardiolipin metabolism in the heart and mammalian cells and to provide insight into their possible implications in the regulation of some cellular functions in mammalian tissues and cells.