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Abstract

The central role of mitochondria in metabolic pathways and in cell-death mechanisms requires sophisticated signalling systems. Essential in this signalling process is an array of lipid mediators derived from polyunsaturated fatty acids. However, the molecular machinery for the production of oxygenated polyunsaturated fatty acids is localized in the cytosol and their biosynthesis has not been identified in mitochondria. Here we report that a range of diversified polyunsaturated molecular species derived from a mitochondria-specific phospholipid, cardiolipin (CL), is oxidized by the intermembrane-space haemoprotein, cytochrome c. We show that a number of oxygenated CL species undergo phospholipase A2-catalysed hydrolysis and thus generate multiple oxygenated fatty acids, including well-known lipid mediators. This represents a new biosynthetic pathway for lipid mediators. We demonstrate that this pathway, which includes the oxidation of polyunsaturated CLs and accumulation of their hydrolysis products (oxygenated linoleic, arachidonic acids and monolysocardiolipins), is activated in vivo after acute tissue injury.

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Acknowledgements

We are thankful to J. L. Millan and S. Narisawa for providing the t-cyt c-specific antibody. We acknowledge support from the National Institutes of Health (ES020693, ES021068, U19AIO68021, PO1 HL114453, NS076511, NS061817, NS052315), the National Institute for Occupational Safety and Health (OH008282), the National Center for Research Resources (S10RR023461), the Human Frontier Science Program (HFSP-RGP0013/2014) and the Fulbright US/Canada Scholar Program.

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Affiliations

  1. Center for Free Radical and Antioxidant Health University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA

    • Yulia Y. Tyurina
    • , Vladimir A. Tyurin
    • , Alexander A. Kapralov
    • , Jianfei Jiang
    • , Tamil Selvan Anthonymuthu
    • , Valentina I. Kapralova
    • , Anna S. Vikulina
    • , Mi-Yeon Jung
    • , Hülya Bayır
    •  & Valerian E. Kagan
  2. Department of Environmental Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA

    • Yulia Y. Tyurina
    • , Vladimir A. Tyurin
    • , Alexander A. Kapralov
    • , Jianfei Jiang
    • , Valentina I. Kapralova
    • , Anna S. Vikulina
    • , Mi-Yeon Jung
    • , Bruce R. Pitt
    •  & Valerian E. Kagan
  3. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA

    • Samuel M. Poloyac
  4. Departments of Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA

    • Tamil Selvan Anthonymuthu
    • , Travis C. Jackson
    • , Patrick M. Kochanek
    •  & Hülya Bayır
  5. Department of Biophysics, MV Lomonosov Moscow State University, Moscow 117192, Russia

    • Anna S. Vikulina
    •  & Yury A. Vladimirov
  6. Radiation Oncology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA

    • Michael W. Epperly
    •  & Joel S. Greenberger
  7. Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA

    • Dariush Mohammadyani
    •  & Bruce R. Pitt
  8. Division of Metabolic and Vascular Health, University of Warwick, Coventry CV4 7AL, UK

    • Judith Klein-Seetharaman

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Contributions

Y.Y.T. designed experiments, performed the MS analysis of CL and its oxidation and hydrolysis products in vivo and in vitro and co-wrote the manuscript, S.M.P. performed MS analysis of oxygenated species of arachidonic acid, V.A.T. performed experiments on CL hydrolysis by LpPLA2 and MS analysis of CL and its hydrolysis products in the small intestine and cells, A.A.K. performed experiments on peroxidase activity of cyt c/CL complexes, J.J. performed the experiments on knocking down t-cyt c, T.S.A. and V.I.K. participated in the MS analysis of CL and its oxidation and hydrolysis products, A.S.V. and M-Y.J. performed cell and mitochondria experiments, D.M. and J.K.S. performed computational analysis of s-cyt c and t-cyt c, M.W.E. and J.S.G. contributed to the design and performance of the in vivo experiment (WBI), T.C.J. and P.M.K. participated in the design and performance of the in vitro experiments with neurons and astrocytes, Y.A.V. and B.R.P. participated in discussion of the results on LC/MS and aspects of the work with the hydrolysis of CLox, H.B. contributed to the formulation of the initial concept of the study, designed and participated in the performance of the in vivo experiment (CCI) and co-wrote the manuscript, and V.E.K. suggested the idea, designed the study and wrote the manuscript. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Yulia Y. Tyurina or Hülya Bayır or Valerian E. Kagan.

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DOI

https://doi.org/10.1038/nchem.1924

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