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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The authors would like to thank J. Lewis for the technical assistance of unbiased stereology for cortical lesion volume, J. Davoren for the preparation of XJB-5-131 and Y.M. Frapart (Laboratoire de Chimie Biochimie Pharmacologique et Toxicologique, Université Paris Descartes) for providing an L-band EPR spectrometer for in vivo imaging. This study was supported in part by grants from the US National Institutes of Health (NS061817 (H.B.), NS060005 (A.E.K.), HL070755 (V.E.K.), ES020693 (Y.Y.T. and V.E.K.), NS076511 and U19AI068021 (H.B. and V.E.K.)), the US National Institute for Occupational Safety and Health (OH008282 to V.E.K.) and the US Army (W81XWH-09-0187 to P.M.K.). A.K.S.-A. is a recipient of a research fellowship from La Junta de Extremadura y el Fondo Social Europeo (2010063090).
The authors declare no competing financial interests.
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