Lipidomics identifies cardiolipin oxidation as a mitochondrial target for redox therapy of brain injury

1] Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. [2] Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. [3] Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. [4] Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Nature Neuroscience (Impact Factor: 16.1). 08/2012; 15(10):1407-13. DOI: 10.1038/nn.3195
Source: PubMed


The brain contains a highly diversified complement of molecular species of a mitochondria-specific phospholipid, cardiolipin, which, because of its polyunsaturation, can readily undergo oxygenation. Using global lipidomics analysis in experimental traumatic brain injury (TBI), we found that TBI was accompanied by oxidative consumption of polyunsaturated cardiolipin and the accumulation of more than 150 new oxygenated molecular species of cardiolipin. RNAi-based manipulations of cardiolipin synthase and cardiolipin levels conferred resistance to mechanical stretch, an in vitro model of traumatic neuronal injury, in primary rat cortical neurons. By applying a brain-permeable mitochondria-targeted electron scavenger, we prevented cardiolipin oxidation in the brain, achieved a substantial reduction in neuronal death both in vitro and in vivo, and markedly reduced behavioral deficits and cortical lesion volume. We conclude that cardiolipin oxygenation generates neuronal death signals and that prevention of it by mitochondria-targeted small molecule inhibitors represents a new target for neuro-drug discovery.

Download full-text


Available from: Jeffrey P Cheng, Feb 11, 2014
  • Source
    • "Both methods independently suggested a very high level of mitochondrial enrichment of XJB, up to 600-fold versus the cytosolic fraction [29] [34]. XJB associates closely with the mitochondria-specific phospholipid cardiolipin and is very efficient in preventing its oxidation [29]. While the mitochondrial membrane targeting sequence of the neutral, acyclic XJB is conceptually derived from the cationic, antimicrobial cyclodecapeptide gramicidin S, it does not permeabilize cell membranes or have antibacterial activity, which is not surprising since gramicidin S-like cell lysis requires a relatively rigid β-sheet conformation that positions cationic and hydrophobic side chains on opposite faces [35]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondria-generated reactive oxygen species (ROS) play a crucial role in the pathogenesis of aging and age-associated diseases. In this study, we evaluated the effects of XJB-5-131 (XJB), a mitochondria-targeted ROS and electron scavenger, on cardiac resistance to ischemia-reperfusion (IR)-induced oxidative stress in aged rats. Male adult (5-month old, n = 17) and aged (29-month old, n = 19) Fischer Brown Norway (F344/BN) rats were randomly assigned to the following groups: adult (A), adult + XJB (AX), aged (O), and aged + XJB (OX). XJB was administered 3 times per week (3 mg/kg body weight, IP) for four weeks. At the end of the treatment period, cardiac function was continuously monitored in excised hearts using the Langendorff technique for 30 min, followed by 20 min of global ischemia, and 60-min reperfusion. XJB improved post-ischemic recovery of aged hearts, as evidenced by greater left ventricular developed-pressures and rate-pressure products than the untreated, aged-matched group. The state 3 respiration rates at complexes I, II and IV of mitochondria isolated from XJB-treated aged hearts were 57% (P< 0.05), 25% (P< 0.05) and 28% (P< 0.05), respectively, higher than controls. Ca2+-induced swelling, an indicator of permeability transition pore opening, was reduced in the mitochondria of XJB-treated aged rats. In addition, XJB significantly attenuated the H2O2-induced depolarization of the mitochondrial inner membrane as well as the total and mitochondrial ROS levels in cultured cardiomyocytes. This study underlines the importance of mitochondrial ROS in aging-induced cardiac dysfunction and suggests that targeting mitochondrial ROS may be an effective therapeutic approach to protect the aged heart against IR injury.
    Full-text · Article · Oct 2014 · Journal of Molecular and Cellular Cardiology
  • Source
    • "70% of the entire metabolome, deciphering the lipidome in terms of biological pathways remains an enormous task. Nonetheless, ultimately lipidomics will increase our understanding of cellular processes (Norris & Dennis 2014) and will lead to the discovery of novel therapeutic targets and biomarkers (Rhee et al. 2011, Ji et al. 2012). On top of that extensive cross-talk between metabolic pathways, on the one hand, and inflammatory and immuno-modulatory pathways, on the other, has been uncovered. "
    [Show abstract] [Hide abstract]
    ABSTRACT: From the viewpoint of the prevention of cardiovascular disease (CVD) burden, there has been a continuous interest in the detrimental effects of the Western-type high-fat diet for more than half a century. More recently, this general view has been subject to change as epidemiological studies showed that replacing fat by carbohydrate may even be worse and that various polyunsaturated fatty acids (FA) have beneficial rather than detrimental effects on CVD outcome. At the same time advances in lipid biology have provided insight into the mechanisms by which the different lipid components of the Western diet affect the cardiovascular system. In fact, this still is a rapidly growing field of research and in recent years novel FA derivatives and FA receptors have been discovered. This includes fish-oil derived FA-derivatives with anti-inflammatory properties, the so-called resolvins, and various G-protein coupled receptors that recognize FA as ligands. In the present review we will extensively discuss the role of FA and their metabolites on cardiac disease, with special emphasis on the role of the different saturated and polyunsaturated FA and their respective metabolites in cellular signal transduction and the possible implications for the development of cardiac hypertrophy and cardiac failure This article is protected by copyright. All rights reserved.
    Full-text · Article · Apr 2014 · Acta Physiologica
  • Source
    • "Cardiolipins (CLs) are tetra-acylated glycerophospholipids that are part of the inner mitochondrial membranes in eukaryotic cells. CLs regulate energy production [12], [13], whereas free radical oxidation products of CLs are important mediators of mitochondria-dependent apoptosis [14]–[16]. Altered levels and composition of CLs are linked to diseases, such as diabetes [13], heart failure [13], [17], Parkinson disease [18], and a rare cardiomyopathy, known as Barth syndrome [19]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Articular synovial fluid (SF) is a complex mixture of components that regulate nutrition, communication, shock absorption, and lubrication. Alterations in its composition can be pathogenic. This lipidomic investigation aims to quantify the composition of sphingolipids (sphingomyelins, ceramides, and hexosyl- and dihexosylceramides) and minor glycerophospholipid species, including (lyso)phosphatidic acid, (lyso)phosphatidylglycerol, and bis(monoacylglycero)phosphate species, in the SF of knee joints from unaffected controls and from patients with early (eOA) and late (lOA) stages of osteoarthritis (OA), and rheumatoid arthritis (RA). SF without cells and cellular debris from 9 postmortem donors (control), 18 RA, 17 eOA, and 13 lOA patients were extracted to measure lipid species using electrospray ionization tandem mass spectrometry - directly or coupled with hydrophilic interaction liquid chromatography. We provide a novel, detailed overview of sphingolipid and minor glycerophospholipid species in human SF. A total of 41, 48, and 50 lipid species were significantly increased in eOA, lOA, and RA SF, respectively when compared with normal SF. The level of 21 lipid species differed in eOA SF versus SF from lOA, an observation that can be used to develop biomarkers. Sphingolipids can alter synovial inflammation and the repair responses of damaged joints. Thus, our lipidomic study provides the foundation for studying the biosynthesis and function of lipid species in health and most prevalent joint diseases.
    Full-text · Article · Mar 2014 · PLoS ONE
Show more