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Cardiolipins are phospholipids that are central to proper mitochondrial functioning. Because mitochondria play crucial roles in differentiation, development, and maturation, we would also expect cardiolipin to play major roles in these processes. Indeed, cardiolipin has been implicated in the mechanism of three human diseases that affect young infants, implying developmental abnormalities. In this review, we will: (1) Review the biology of cardiolipin; (2) Outline the evidence for essential roles of cardiolipin during organismal development, including embryogenesis and cell maturation in vertebrate organisms; (3) Place the role(s) of cardiolipin during embryogenesis within the larger context of the roles of mitochondria in development; and (4) Suggest avenues for future research. Key Findings: As the "signature" phospholipid in mitochondria, we would expect cardiolipin to play a major role in developmental processes.Indeed, three human mitochondrial diseases now implicate cardiolipin primarily in their pathogenesis, affecting young infants and therefore displaying developmental abnormalities.Here, we will review the biology of cardiolipin, and the evidence for evolving and essential roles of cardiolipin during organismal development, including embryogenesis and cell maturation.In addition to studies in cellular model systems, we will establish that cardiolipin plays a role in vertebrate development and outline the evidence for possible underlying mechanisms. [ABSTRACT FROM AUTHOR]

Mitochondrial cristae are extraordinarily crowded with proteins, which puts stress on the bilayer organization of lipids. We tested the hypothesis that the high concentration of proteins drives the tafazzin‐catalyzed remodeling of fatty acids in cardiolipin, thereby reducing bilayer stress in the membrane. Specifically, we tested whether protein crowding induces cardiolipin remodeling and whether the lack of cardiolipin remodeling prevents the membrane from accumulating proteins. In vitro, the incorporation of large amounts of proteins into liposomes altered the outcome of the remodeling reaction. In yeast, the concentration of proteins involved in oxidative phosphorylation (OXPHOS) correlated with the cardiolipin composition. Genetic ablation of either remodeling or biosynthesis of cardiolipin caused a substantial drop in the surface density of OXPHOS proteins in the inner membrane of the mouse heart and Drosophila flight muscle mitochondria. Our data suggest that OXPHOS protein crowding induces cardiolipin remodelling and that remodeled cardiolipin supports the high concentration of these proteins in the inner mitochondrial membrane. SYNOPSIS: In mitochondrial cristae, proteins are packaged at uniquely high density, imposing stress on the membrane lipid composition. This work uncovers acyl group remodeling of the membrane phospholipid cardiolipin as a precondition for concentrating oxidative phosphorylation (OXPHOS) proteins in the inner mitochondrial membrane. Protein crowding affects fatty acid remodeling of cardiolipin in vitro.The surface concentration of OXPHOS proteins correlates with the molecular species composition of cardiolipin.Ablation of cardiolipin remodeling or biosynthesis decreases surface concentration of OXPHOS proteins in mice and flies. [ABSTRACT FROM AUTHOR]

Background: The PGC-1α/PPAR axis has been proposed as a potential therapeutic target for several metabolic disorders. The aim was to evaluate the efficacy of the pan-PPAR agonist, bezafibrate, in tafazzin knockdown mice (TazKD), a mouse model of Barth syndrome that exhibits age-dependent dilated cardiomyopathy with left ventricular (LV) dysfunction.Results: The effect of bezafibrate on cardiac function was evaluated by echocardiography in TazKD mice with or without beta-adrenergic stress. Adrenergic stress by chronic isoproterenol infusion exacerbates the cardiac phenotype in TazKD mice, significantly depressing LV systolic function by 4.5 months of age. Bezafibrate intake over 2 months substantially ameliorates the development of LV systolic dysfunction in isoproterenol-stressed TazKD mice. Without beta-adrenergic stress, TazKD mice develop dilated cardiomyopathy by 7 months of age. Prolonged treatment with suprapharmacological dose of bezafibrate (0.5% in rodent diet) over a 4-month period effectively prevented LV dilation in mice isoproterenol treatment. Bezafibrate increased mitochondrial biogenesis, however also promoted oxidative stress in cardiomyocytes. Surprisingly, improvement of systolic function in bezafibrate-treated mice was accompanied with simultaneous reduction of cardiolipin content and increase of monolysocardiolipin levels in cardiac muscle.Conclusions: Thus, we demonstrate that bezafibrate has a potent therapeutic effect on preventing cardiac dysfunction in a mouse model of Barth syndrome with obvious implications for treating the human disease. Additional studies are needed to assess the potential benefits of PPAR agonists in humans with Barth syndrome. [ABSTRACT FROM AUTHOR]

Respiratory complexes and cardiolipins have exceptionally long lifetimes. The fact that they co-localize in mitochondrial cristae raises the question of whether their longevities have a common cause and whether the longevity of OXPHOS proteins is dependent on cardiolipin. To address these questions, we developed a method to measure side-by-side the half-lives of proteins and lipids in wild-type Drosophila and cardiolipindeficient mutants. We fed adult flies with stable isotopelabeled precursors (13C6 15N2-lysine or 13C6-glucose) and determined the relative abundance of heavy isotopomers in protein and lipid species by mass spectrometry. To minimize the confounding effects of tissue regeneration, we restricted our analysis to the thorax, the bulk of which consists of post-mitotic flight muscles. Analysis of 680 protein and 45 lipid species showed that the subunits of respiratory complexes I-V and the carriers for phosphate and ADP/ATP were among the longestlived proteins (average half-life of 48 ± 16 days) while the molecular species of cardiolipin were the longest-lived lipids (average half-life of 27 ± 6 days). The remarkable longevity of these crista residents was not shared by all mitochondrial proteins, especially not by those residing in the matrix and the inner boundary membrane. Ablation of cardiolipin synthase, which causes replacement of cardiolipin by phosphatidylglycerol, and ablation of tafazzin, which causes partial replacement of cardiolipin by monolyso-cardiolipin, decreased the lifetimes of the respiratory complexes. Ablation of tafazzin also decreased the lifetimes of the remaining cardiolipin species. These data suggest that an important function of cardiolipin in mitochondria is to protect respiratory complexes from degradation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Mitochondria contain cardiolipin (CL), an organelle-specific phospholipid that carries four fatty acids with a strong preference for unsaturated chains. Unsaturation is essential for the stability and for the function of mitochondrial CL. Surprisingly, we found tetrapalmitoyl-CL (TPCL), a fully saturated species, in the testes of humans and mice. TPCL was absent from other mouse tissues but was the most abundant CL species in testicular germ cells. Most intriguingly, TPCL was not localized in mitochondria but was in other cellular membranes even though mitochondrial CL was the substrate from which TPCL was synthesized. During spermiogenesis, TPCL became associated with the acrosome, a sperm-specific organelle, along with a subset of authentic mitochondrial proteins, including Ant4, Suox, and Spata18. Our data suggest that mitochondria-derived membranes are assembled into the acrosome, challenging the concept that this organelle is strictly derived from the Golgi apparatus and revealing a novel function of mitochondria. [ABSTRACT FROM AUTHOR]