title: Formation of electrophilic oxidation products from mitochondrial cardiolipin in vitro and in vivo in the context of apoptosis and atherosclerosis.
abstract: Emerging evidence indicates that mitochondrial cardiolipins (CL) are prone to free radical oxidation and this process appears to be intimately associated with multiple biological functions of mitochondria. Our previous work demonstrated that a significant amount of potent lipid electrophiles including 4-hydroxy-nonenal (4-HNE) was generated from CL oxidation through a novel chemical mechanism. Here we provide further evidence that a characteristic class of CL oxidation products, epoxyalcohol-aldehyde-CL (EAA-CL), is formed through this novel mechanism in isolated mice liver mitochondria when treated with the pro-apoptotic protein t-Bid to induce cyt c release. Generation of these oxidation products are dose-dependently attenuated by a peroxidase inhibitor acetaminophen (ApAP). Using a mouse model of atherosclerosis, we detected significant amount of these CL oxidation products in liver tissue of low density lipoprotein receptor knockout (LDLR -/-) mice after Western diet feeding. Our studies highlight the importance of lipid electrophiles formation from CL oxidation in the settings of apoptosis and atherosclerosis as inhibition of CL oxidation and lipid electrophiles formation may have potential therapeutic value in diseases linked to oxidant stress and mitochondrial dysfunctions.
authors: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences (INS), Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, China ; University of the Chinese Academy of Sciences, CAS, Beijing, China ; Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, China.
authors: Huiqin
authors: H
authors: Zhong
authors: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences (INS), Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, China ; University of the Chinese Academy of Sciences, CAS, Beijing, China ; Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, China.
authors: Jianhong
authors: J
authors: Lu
authors: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences (INS), Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, China ; Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, China.
authors: Lin
authors: L
authors: Xia
authors: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences (INS), Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, China ; Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, China.
authors: Mingjiang
authors: M
authors: Zhu
authors: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences (INS), Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, China ; University of the Chinese Academy of Sciences, CAS, Beijing, China ; Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, China ; School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
authors: Huiyong
authors: H
authors: Yin
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001161:Arteriosclerosis / Q000378:metabolism / Q000473:pathology; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D002308:Cardiolipins / Q000032:analysis / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D059305:Diet, High-Fat; D008099:Liver / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D002308:Cardiolipins; D011973:Receptors, LDL; D000082:Acetaminophen
keywords: 4-HNE, 4-hydroxy-nonena; 4-ONE, 4-oxo-2-nonenal; 4-hydroxy-2-nonenal (4-HNE); ALDH2, aldehyde dehydrogenase-2; ApAP, acetaminophen; Apoptosis; Atherosclerosis; BHT, butylate hydroxytoluene; CL, cardiolipin cyt c cytochrome c; Cardiolipin; EAA-CL, epoxyalcohol-aldehyde-CL; ESI, electrospray; ETC, electron transport chain; Epoxyalcohol-aldehyde-CL (EAA-CL); H2O2, hydrogen peroxide; HODE, hydroxyoctadienoic acid; HpODE, hydroperoxyoctadecadienoic acid; KODE, keto-octadecadienoic acid; L3OCL, trilinoleoyl oleoyl cardiolipin; L4CL, tetralinoleoyl cardiolipin; LA, linoleic acid; LC–MS, liquid chromatography–mass spectrometry; LDLR −/−, low density lipoprotein receptor knockout; Lipid peroxidation; Liquid chromatography–mass spectrometry (LC–MS); M4CL, tetramyristeoyl cardiolipin; MRM, multiple reaction monitoring; Mitochondria; PHGPX, hospholipid hydroperoxide glutathione peroxidase; PUFAs, Polyunsaturated fatty acids; Prdx3/Prx3, peroxiredoxin 3; ROS, reactive oxygen species