title: Lipidomics identifies cardiolipin oxidation as a mitochondrial target for redox therapy of brain injury.
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.
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Ji
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Kline
authors.forename: Andrew
authors.initials: A
authors.lastname: Amoscato
authors.forename: Alejandro K
authors.initials: AK
authors.lastname: Samhan-Arias
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Sparvero
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Tyurin
authors.forename: Yulia Y
authors.initials: YY
authors.lastname: Tyurina
authors.forename: Bruno
authors.initials: B
authors.lastname: Fink
authors.forename: Mioara D
authors.initials: MD
authors.lastname: Manole
authors.forename: Ava M
authors.initials: AM
authors.lastname: Puccio
authors.forename: David O
authors.initials: DO
authors.lastname: Okonkwo
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Cheng
authors.forename: Henry
authors.initials: H
authors.lastname: Alexander
authors.forename: Robert S B
authors.initials: RS
authors.lastname: Clark
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kochanek
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
authors.forename: Valerian E
authors.initials: VE
authors.lastname: Kagan
authors.forename: Hülya
authors.initials: H
authors.lastname: Bayır
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002308:Cardiolipins / Q000378:metabolism / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003497:Cyclic N-Oxides / Q000494:pharmacology / Q000627:therapeutic use*; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010084:Oxidation-Reduction; D061251:Primary Cell Culture; D051381:Rats; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics / Q000378:metabolism
chemical_list: D002308:Cardiolipins; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D008565:Membrane Proteins; C523959:XJB-5-131; D017855:Transferases (Other Substituted Phosphate Groups); C100091:cardiolipin synthetase