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.

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Available from: Jeffrey P Cheng, Feb 11, 2014
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    • "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]. "
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