A mitochondrial pathway for biosynthesis of lipid mediators.
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.
1] Center for Free Radical and Antioxidant Health University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA [2] Department of Environmental Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Yulia Y
YY
Tyurina
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Samuel M
SM
Poloyac
1] Center for Free Radical and Antioxidant Health University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA [2] Department of Environmental Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Vladimir A
VA
Tyurin
1] Center for Free Radical and Antioxidant Health University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA [2] Department of Environmental Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Alexander A
AA
Kapralov
1] Center for Free Radical and Antioxidant Health University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA [2] Department of Environmental Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Jianfei
J
Jiang
1] Center for Free Radical and Antioxidant Health University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA [2] Departments of Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Tamil Selvan
TS
Anthonymuthu
1] Center for Free Radical and Antioxidant Health University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA [2] Department of Environmental Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Valentina I
VI
Kapralova
1] Center for Free Radical and Antioxidant Health University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA [2] Department of Environmental Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA [3] Department of Biophysics, MV Lomonosov Moscow State University, Moscow 117192, Russia.
Anna S
AS
Vikulina
1] Center for Free Radical and Antioxidant Health University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA [2] Department of Environmental Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Mi-Yeon
MY
Jung
Radiation Oncology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Michael W
MW
Epperly
Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Dariush
D
Mohammadyani
Division of Metabolic and Vascular Health, University of Warwick, Coventry CV4 7AL, UK.
Judith
J
Klein-Seetharaman
Departments of Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Travis C
TC
Jackson
Departments of Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Patrick M
PM
Kochanek
1] Department of Environmental Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA [2] Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Bruce R
BR
Pitt
Radiation Oncology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Joel S
JS
Greenberger
Department of Biophysics, MV Lomonosov Moscow State University, Moscow 117192, Russia.
Yury A
YA
Vladimirov
1] Center for Free Radical and Antioxidant Health University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA [2] Departments of Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Hülya
H
Bayır
1] Center for Free Radical and Antioxidant Health University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA [2] Department of Environmental Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Valerian E
VE
Kagan
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D002118:Calcium / Q000378:metabolism; D002308:Cardiolipins / Q000737:chemistry* / Q000378:metabolism*; D002853:Chromatography, Liquid; D045304:Cytochromes c / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D005260:Female; D054513:Group IV Phospholipases A2 / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007421:Intestine, Small / Q000187:drug effects / Q000293:injuries / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction; D051381:Rats; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014916:Whole-Body Irradiation
D002308:Cardiolipins; D005231:Fatty Acids, Unsaturated; D008246:Lysophospholipids; D016877:Oxidants; C067188:monolysocardiolipin; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D054513:Group IV Phospholipases A2; D002118:Calcium