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

Nature Neuroscience volume 15, pages 14071413 (2012) | Download Citation

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Abstract

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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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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Acknowledgements

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

Affiliations

  1. Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Jing Ji
    • , Henry Alexander
    • , Robert S B Clark
    • , Patrick M Kochanek
    •  & Hülya Bayır
  2. Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Jing Ji
    • , Andrew Amoscato
    • , Alejandro K Samhan-Arias
    • , Louis J Sparvero
    • , Vladimir A Tyurin
    • , Yulia Y Tyurina
    • , Valerian E Kagan
    •  & Hülya Bayır
  3. Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Jing Ji
    • , Andrew Amoscato
    • , Alejandro K Samhan-Arias
    • , Louis J Sparvero
    • , Vladimir A Tyurin
    • , Yulia Y Tyurina
    • , Valerian E Kagan
    •  & Hülya Bayır
  4. Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Jing Ji
    • , Anthony E Kline
    • , Mioara D Manole
    • , Jeffrey P Cheng
    • , Henry Alexander
    • , Robert S B Clark
    • , Patrick M Kochanek
    •  & Hülya Bayır
  5. Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Anthony E Kline
    •  & Jeffrey P Cheng
  6. Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Anthony E Kline
  7. Noxygen Science Transfer and Diagnostics GmbH, Elzach, Germany.

    • Bruno Fink
  8. Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

    • Mioara D Manole
    • , Robert S B Clark
    • , Patrick M Kochanek
    •  & Hülya Bayır
  9. Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Ava M Puccio
    •  & David O Okonkwo
  10. Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Peter Wipf

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Hülya Bayır.

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DOI

https://doi.org/10.1038/nn.3195

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