Deciphering of mitochondrial cardiolipin oxidative signaling in cerebral ischemia-reperfusion

Details

• Personal Author:
  Anthonymuthu TS ; Baart S ; Bayir H ; Clark RSB ; Du L ; Ji J ; Kagan VE ; Kline AE ; Kochanek PM ; Lewis J ; Skoda EM ; St Croix CM ; Tyurin VA ; Tyurina YY ; Vikulina AS ; Wipf P
• Description:
  It is believed that biosynthesis of lipid mediators in the central nervous system after cerebral ischemia-reperfusion starts with phospholipid hydrolysis by calcium-dependent phospholipases and is followed by oxygenation of released fatty acids (FAs). Here, we report an alternative pathway whereby cereberal ischemia-reperfusion triggered oxygenation of a mitochondria-specific phospholipid, cardiolipin (CL), is followed by its hydrolysis to yield monolyso-CLs and oxygenated derivatives of fatty (linoleic) acids. We used a model of global cerebral ischemia-reperfusion characterized by 9 minutes of asphyxia leading to asystole followed by cardiopulmonary resuscitation in postnatal day 17 rats. Global ischemia and cardiopulmonary resuscitation resulted in: (1) selective oxidation and hydrolysis of CLs, (2) accumulation of lyso-CLs and oxygenated free FAs, (3) activation of caspase 3/7 in the brain, and (4) motor and cognitive dysfunction. On the basis of these findings, we used a mitochondria targeted nitroxide electron scavenger, which prevented CL oxidation and subsequent hydrolysis, attenuated caspase activation, and improved neurocognitive outcome when administered after cardiac arrest. These data show that calcium-independent CL oxidation and subsequent hydrolysis represent a previously unidentified pathogenic mechanism of brain injury incurred by ischemia-reperfusion and a clinically relevant therapeutic target. [Description provided by NIOSH]
• Subjects:
  Blood Cardiovascular System Energy Metabolism Laboratories Lipids Nervous System Nervous System Diseases Occupational Health Pathology Safety
• Keywords:
  Biosynthesis Blood-vessels Brain-damage Brain-function Cell-metabolism Central-nervous-system Cerebrovascular-system Fatty-acids Laboratory-animals Laboratory-testing Metabolism Oxidative-processes Phospholipids Plasma-membrane Tissue-disorders

  More +
• ISSN:
  0271-678X
• 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
• Pages in Document:
  319-328
• Volume:
  35
• Issue:
  2
• NIOSHTIC Number:
  nn:20046076
• Citation:
  J Cereb Blood Flow Metab 2015 Feb; 35(2):319-328
• Federal Fiscal Year:
  2015
• NORA Priority Area:
  Manufacturing
• Performing Organization:
  University of Pittsburgh at Pittsburgh
• Peer Reviewed:
  True
• Start Date:
  20050701
• Source Full Name:
  Journal of Cerebral Blood Flow and Metabolism
• End Date:
  20160630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:c96dad886178fea5d4b14575a24f44868657baf350a2f7ede4c9177b28f187dab4d0534cb81ac348ce7f62a312f45252e2643c45623a47085327f2c738946ba1
• Download URL:
  https://stacks.cdc.gov/view/cdc/201249/cdc_201249_DS1.pdf
• File Type:
  [PDF - 750.29 KB ]