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

Details

• Personal Author:
  Alexander H ; Amoscato A ; Bayir H ; Cheng JP ; Clark RSB ; Fink B ; Ji J ; Kagan VE ; Kline AE ; Kochanek PM ; Manole MD ; Okonkwo DO ; Puccio AM ; Samhan-Arias AK ; Sparvero LJ ; Tyurin VA ; Tyurina YY ; Wipf P
• 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. [Description provided by NIOSH]
• Subjects:
  Animals Behavior Cardiovascular Diseases Cardiovascular System Energy Metabolism Genetics Laboratories Nervous System Nervous System Diseases Nervous System Disorders Occupational Health Pathology Safety

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• Keywords:
  Brain-function Cell-biology Cell-function Central-nervous-system Central-nervous-system-disorders Cerebrovascular-system Cerebrovascular-system-disorders Drugs Injuries Laboratory-animals Metabolism Pharmacology Physiology Physiopathology Proteins

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• ISSN:
  1097-6256
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; Pennsylvania
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  15
• Issue:
  10
• NIOSHTIC Number:
  nn:20041901
• Citation:
  Nat Neurosci 2012 Oct; 15(10):1407-1413
• Email:
  bayihx@ccm.upmc.edu
• Federal Fiscal Year:
  2013
• NORA Priority Area:
  Manufacturing
• Performing Organization:
  University of Pittsburgh at Pittsburgh
• Peer Reviewed:
  True
• Start Date:
  20050701
• Source Full Name:
  Nature Neuroscience
• End Date:
  20160630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:584502ff82b33a2f40fc928b562d20c4b38f6f5f9308ad858d446e2b24ed00033bba44e6a87843fbe781e3fccd4488d316e95d027410e26ee496d5c743e3ddae
• Download URL:
  https://stacks.cdc.gov/view/cdc/194324/cdc_194324_DS1.pdf
• File Type:
  [PDF - 1.00 MB ]