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Mitochondrial cardiolipin as a substrate for cytochrome c-catalyzed production of oxygenated lipid mediators.

Kagan-V; Tyurin-V; Poloyac-S; Epperly-M; Greenberger-J; Bayir-H; Tyurina-Y
Toxicologist 2013 Mar; 132(1):428
Lipid mediators - central to the normal homeostasis and responses to stress and disease - are generated through oxygenation of polyunsaturated fatty acids (PUFA), such as linoleic acid (LA), arachidonic acid (AA) and docosahexaenoic acid. Their regulatory effects are believed to depend on a fine balance between PUFA esterification/reacylation of phospholipids and on their hydrolysis by phospholipases A (PLA). We suggested that mitochondrial cardiolipins (CLs) can be a source of bioactive lipid mediators generated with the catalytic participation of cytochrome c (cyt c). In this study we employed models of rat traumatic brain injury (TBI) and mouse total body irradiation (TIR). Using oxidative lipidomics approach and MS/MS analysis, we found that TBI resulted in oxidation of polyunsaturated molecular species of CL and accumulation of its hydrolysis products such as oxygenated LA, AA and monolyso-CL. Similar, a significant increase of oxidized CLs in small intestine of TIR mice (9.5 Gy) was accompanied by accumulation of CL hydrolysis products. To generate oxygenated CL in vitro we utilized brain CL, with its highly diversified polyunsaturated molecular species, and cyt c. We found that incubation of brain CL with cyt c in the presence of H2O2 yields a rich assortment of oxygenated CL species, hydrolysis of which by PLA1 and A2 generated multiple oxygenated fatty acids similar to those that were formed in vivo in brain after TBI and small intestine after TIR. An oxidation-specific lipoprotein lipase A2, was able to utilize peroxidized tetralinoleoy-CL to yield different oxygenated species of linoleic acid and lyso-CLs. Thus, mitochondrial CL/cyt c represents a novel mechanisms involved in lipid mediators-generating pathways.
Toxicology; Laboratory-animals; Laboratory-techniques; Laboratory-testing; Lipids; Fatty-acids; Cellular-function; Cellular-reactions; Oxidative-processes; Acids; Phospholipids; Lipases; Bioactivation; Cytochemistry; Mass-spectrometry; Analytical-models; Oxidation; Intestinal-cells; In-vitro-study; Proteins
Publication Date
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Identifying No.
Grant-Number-R01-OH-008282; B20130502
Issue of Publication
Source Name
The Toxicologist. Society of Toxicology 52nd Annual Meeting and ToxExpo, March 10-14, 2013, San Antonio, Texas
Performing Organization
University of Pittsburgh at Pittsburgh