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

Authors
Ji-J; Kline-AE; Amoscato-A; Samhan-Arias-AK; Sparvero-LJ; Tyurin-VA; Tyurina-YY; Fink-B; Manole-MD; Puccio-AM; Okonkwo-DO; Cheng-JP; Alexander-H; Clark-RSB; Kochanek-PM; Wipf-P; Kagan-VE; Bayir-H
Source
Nat Neurosci 2012 Oct; 15(10):1407-1413
NIOSHTIC No.
20041901
Abstract
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.
Keywords
Brain-function; Behavior; Animals; Laboratory-animals; Injuries; Pathology; Metabolism; Physiopathology; Physiology; Cell-function; Cell-biology; Drugs; Cerebrovascular-system; Cerebrovascular-system-disorders; Pharmacology; Proteins; Genetics; Central-nervous-system; Central-nervous-system-disorders
CODEN
NANEFN
Publication Date
20121015
Document Type
Journal Article
Email Address
bayihx@ccm.upmc.edu
Funding Type
Grant
Fiscal Year
2013
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-008282; B20130124
Issue of Publication
10
ISSN
1097-6256
Source Name
Nature Neuroscience
State
PA
Performing Organization
University of Pittsburgh at Pittsburgh
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