Deciphering of mitochondrial cardiolipin oxidative signaling in cerebral ischemia-reperfusion
Ji J, Baart S, Vikulina AS, Clark RSB, Anthonymuthu TS, Tyurin VA, Du L, St Croix CM, Tyurina YY, Lewis J, Skoda EM, Kline AE, Kochanek PM, Wipf P, Kagan VE, Bayir H (2015)
Publication Type: Journal article
Publication year: 2015
Journal
Book Volume: 35
Pages Range: 319-328
Journal Issue: 2
Abstract
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.
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APA:
Ji, J., Baart, S., Vikulina, A.S., Clark, R.S.B., Anthonymuthu, T.S., Tyurin, V.A.,... Bayir, H. (2015). Deciphering of mitochondrial cardiolipin oxidative signaling in cerebral ischemia-reperfusion. Journal of Cerebral Blood Flow and Metabolism, 35(2), 319-328. https://dx.doi.org/10.1038/jcbfm.2014.204
MLA:
Ji, Jing, et al. "Deciphering of mitochondrial cardiolipin oxidative signaling in cerebral ischemia-reperfusion." Journal of Cerebral Blood Flow and Metabolism 35.2 (2015): 319-328.
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