Selective early cardiolipin peroxidation after traumatic brain injury: an oxidative lipidomics analysis.
OBJECTIVE
Enhanced lipid peroxidation is well established in traumatic brain injury. However, its molecular targets, identity of peroxidized phospholipid species, and their signaling role have not been deciphered.


METHODS
Using controlled cortical impact as a model of traumatic brain injury, we employed a newly developed oxidative lipidomics approach to qualitatively and quantitatively characterize the lipid peroxidation response.


RESULTS
Electrospray ionization and matrix-assisted laser desorption/ionization mass spectrometry analysis of rat cortical mitochondrial/synaptosomal fractions demonstrated the presence of highly oxidizable molecular species containing C(22:6) fatty acid residues in all major classes of phospholipids. However, the pattern of phospholipid oxidation at 3 hours after injury displayed a nonrandom character independent of abundance of oxidizable species and included only one mitochondria-specific phospholipid, cardiolipin (CL). This selective CL peroxidation was followed at 24 hours by peroxidation of other phospholipids, most prominently phosphatidylserine, but also phosphatidylcholine and phosphatidylethanolamine. CL oxidation preceded appearance of biomarkers of apoptosis (caspase-3 activation, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling-positivity) and oxidative stress (loss of glutathione and ascorbate).


CONCLUSIONS
The temporal sequence combined with the recently demonstrated role of CL hydroperoxides (CL-OOH) in in vitro models of apoptosis suggest that CL-OOH may be both a key in vivo trigger of apoptotic cell death and a therapeutic target in experimental traumatic brain injury.
Bayir
Hülya
H
Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA. bayihx@ccm.upmc.edu
Tyurin
Vladimir A
VA
Tyurina
Yulia Y
YY
Viner
Rosa
R
Ritov
Vladimir
V
Amoscato
Andrew A
AA
Zhao
Qing
Q
Zhang
Xiaojing J
XJ
Janesko-Feldman
Keri L
KL
Alexander
Henry
H
Basova
Liana V
LV
Clark
Robert S B
RS
Kochanek
Patrick M
PM
Kagan
Valerian E
VE
D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D001930:Brain Injuries / Q000378:metabolism*; D002308:Cardiolipins / Q000378:metabolism*; D002384:Catalysis; D002540:Cerebral Cortex / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D015227:Lipid Peroxidation; D008297:Male; D013058:Mass Spectrometry; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D018384:Oxidative Stress; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013574:Synaptosomes / Q000378:metabolism; D014949:Wounds, Nonpenetrating / Q000378:metabolism
D015415:Biomarkers; D002308:Cardiolipins; D009097:Multienzyme Complexes; D010743:Phospholipids; C523441:tetralinoleoylcardiolipin; D045304:Cytochromes c