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

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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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Figure 1: Assessment of molecular species of cardiolipin and its oxidation products by 2D-LC-MS after TBI.
Figure 2: Response of cardiolipin- or cyt c–deficient neurons to in vitro TBI.
Figure 3: Neuronal cell death in response to non-oxidized and oxidized cardiolipin.
Figure 4: Analysis of XJB-5-131 distribution in neurons and brain.
Figure 5: Assessments of neurobehavioral and histological outcome in P17 rats treated with XJB-5-131 after TBI.
Figure 6: Response of neurons treated with 4-amino-TEMPO to in vitro TBI.
Figure 7: EPR spectroscopy assessment of inter-conversions of nitroxides and hydroxylamines.

Change history

  • 05 September 2012

    In the version of this article initially published online, the name of author Alejandro K. Samhan-Arias was given as Alejandro S. Arias. The error has been corrected for the print, PDF and HTML versions of this article.


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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).

Author information

J.J. designed and performed experiments, analyzed data and wrote the manuscript. A.E.K. and J.P.C. contributed to the neurocognitive outcome assessment and writing of the manuscript. A.A., Y.Y.T. and A.K.S.-A. contributed to the assessment of cardiolipin oxidation by 2D-LC-MS. L.J.S. contributed to the mass spectrometry imaging. V.A.T. contributed to the EPR measurements. B.F. contributed to the in vivo EPR imaging. M.D.M. contributed to the unbiased stereology for cortical lesion volume. A.M.P. and D.O.O. contributed to evaluation of human TBI tissue and writing of the manuscript. H.A. performed in vivo TBI experiments. R.S.B.C. and P.M.K. contributed to data analysis and manuscript writing. P.W. contributed to the preparation of XJB-5-131 and manuscript writing. V.E.K. and H.B. initiated and directed the entire study, designed experiments and wrote the manuscript.

Correspondence to Hülya Bayır.

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