Deciphering of Mitochondrial Cardiolipin Oxidative Signaling in Cerebral Ischemia-Reperfusion

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.

Phospholipid alterations in the brain and heart in a rat model of asphyxia-induced cardiac arrest and cardiopulmonary bypass resuscitation

“…total ischemia vs collateral blood flow, may be responsible for the inconsistent results regarding the decrease in phospholipids due to ischemia. Consistent with this argument and the results reported in our study, complete global brain ischemia by decapitation or CA with 7 day-old rats did not significantly decrease the content of phospholipids [11, 13]. …”

“…Some studies showed a significant decrease in the content of brain phospholipids [8–10, 37], whereas other studies found no change [11, 13], even after 60 min of ischemia [12]. These contradictory findings suggest that ischemia alone is not sufficient to cause significant phospholipid alterations.…”

“…However, the extent of phospholipid loss is controversial, particularly in the brain. Some studies showed a significant decrease in the content of phospholipids following ischemia [8–10], while others showed no change [11–13]. These contradictory results may be attributable to the types of ischemia models, which generate different degree (complete vs incomplete) or area (global vs focal) of ischemia [11, 14]; results from one ischemic model cannot be directly applied to other models.…”

Known unknowns of cardiolipin signaling: The best is yet to come

“…Intriguingly, a very high level of phospholipid specificity has been discovered as one of the most characteristic features of oxidation reactions triggered by these very different stimuli in different tissues with the common denominator – massive apoptosis. Mitochondrial CLs were found universally and most abundantly oxidized during injury associated with these insults [25, 41, 77, 80, 158]. Strikingly, CL oxidation turned to be non-random as well but had a pronounced specificity unrelated to the pattern of CL polyunsaturation.…”

Neuroprotective properties of mitochondria-targeted antioxidants of the SkQ-type

“…Mitochondrial membrane depolarization, ROS production, nitric oxide synthase (iNOS) induction, and nuclear translocation of p65 were significantly reduced in latrepirdine-treated rat hippocampal slices subjected to oxygen and glucose deprivation (OGD) followed by reoxygenation (Egea et al, 2014). Another mitochondria-targeted compound, nitroxide electron scavenger (XJB-5-131), prevented cardiolipin oxidation and subsequent hydrolysis, attenuated caspase activation in the brain, and improved neurocognitive outcome when administered after cardiac arrest (Ji et al, 2015).…”