Global lipidomics identifies cardiolipin oxidation as a mitochondrial target for redox therapy of acute brain injury

Details

• Alternative Title:
  Nat Neurosci
• Personal Author:
  Ji, Jing ; Kline, Anthony E ; Amoscato, Andrew ; Arias, Alejandro S ; Sparvero, Louis J ; Tyurin, Vladimir A ; Tyurina, Yulia Y ; Fink, Bruno ; Manole, Mioara D ; Puccio, Ava M ; Okonkwo, David O ; Cheng, Jeffrey P ; Alexander, Henry ; Clark, Robert SB ; Kochanek, Patrick M ; Wipf, Peter ; Kagan, Valerian E ; Bayýr, Hülya
• Description:
  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.
• Subjects:
  Animals Behavior, Animal Brain Injuries Cardiolipins Cell Death Cerebral Cortex Cyclic N-Oxides Free Radical Scavengers Lipid Peroxidation Membrane Proteins Mitochondria Neurons Oxidation-Reduction Primary Cell Culture Rats Transferases (Other Substituted Phosphate Groups)

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• Source:
  Nat Neurosci. 15(10):1407-1413.
• Pubmed ID:
  22922784
• Pubmed Central ID:
  PMC3697869
• Document Type:
  Journal Article
• Funding:
  ES020693/ES/NIEHS NIH HHS/United States ; HL070755/HL/NHLBI NIH HHS/United States ; NS060005/NS/NINDS NIH HHS/United States ; NS061817/NS/NINDS NIH HHS/United States ; NS076511/NS/NINDS NIH HHS/United States ; OH008282/OH/NIOSH CDC HHS/United States ; R01 ES020693/ES/NIEHS NIH HHS/United States ; R01 HD069620/HD/NICHD NIH HHS/United States ; R01 HL070755/HL/NHLBI NIH HHS/United States ; R01 NS060005/NS/NINDS NIH HHS/United States ; R01 NS061817/NS/NINDS NIH HHS/United States ; R01 NS076511/NS/NINDS NIH HHS/United States ; U19 AI068021/AI/NIAID NIH HHS/United States ; U19AI068021/AI/NIAID NIH HHS/United States
• Volume:
  15
• Issue:
  10
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:7dc75211a1d4a4f07cda1f5017787baba7b56429d642e960e89069f6d88d5108
• Download URL:
  https://stacks.cdc.gov/view/cdc/22589/cdc_22589_DS1.pdf
• File Type:
  [PDF - 725.93 KB ]