Micromolar changes in lysophosphatidylcholine concentration cause minor effects on mitochondrial permeability but major alterations in function

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• 作者：Norris I. Hollie^a ; James G. Cash^a ; M. Abdul Matlib^b ; Matthew Wortman^c ; Joshua E. Basford^a ; William Abplanalp^a ; David Y. Hui^a ; ^{huidy@ucmail.uc.edu" class="auth_mail}
• 关键词：AM ; acetoxymethylester ; CsA ; cyclosporine A ; FCCP ; carbonyl cyanide 4-(trifluoromethoxy) phenyhydrazone ; iPLA2 ; calcium independent phospholipase A2 ; LPC ; lysophosphatidylcholine ; MOPS ; 3-(N-Morpholino)propanesulfonic acid ; MPT ; membrane permeability transition ; OCR ; oxygen consumption rate ; PLA2 ; phospholipase A2 ; PPAR ; peroxisome proliferator-activated receptor ; RCI ; respiratory control index
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids
• 出版年：June, 2014
• 年：2014
• 卷：1841
• 期：6
• 页码：888-895
• 全文大小：1098 K

文摘

Mice deficient in group 1b phospholipase A₂ have decreased plasma lysophosphatidylcholine and increased hepatic oxidation that is inhibited by intraperitoneal lysophosphatidylcholine injection. This study sought to identify a mechanism for lysophosphatidylcholine-mediated inhibition of hepatic oxidative function. Results showed that in vitro incubation of isolated mitochondria with 40-200 渭M lysophosphatidylcholine caused cyclosporine A-resistant swelling in a concentration-dependent manner. However, when mitochondria were challenged with 220 渭M CaCl₂, cyclosporine A protected against permeability transition induced by 40 渭M, but not 80 渭M lysophosphatidylcholine. Incubation with 40-120 渭M lysophosphatidylcholine also increased mitochondrial permeability to 75 渭M CaCl₂ in a concentration-dependent manner. Interestingly, despite incubation with 80 渭M lysophosphatidylcholine, the mitochondrial membrane potential was steady in the presence of succinate, and oxidation rates and respiratory control indices were similar to controls in the presence of succinate, glutamate/malate, and palmitoyl-carnitine. However, mitochondrial oxidation rates were inhibited by 30-50% at 100 渭M lysophosphatidylcholine. Finally, while 40 渭M lysophosphatidylcholine has no effect on fatty acid oxidation and mitochondria remained impermeable in intact hepatocytes, 100 渭M lysophosphatidylcholine inhibited fatty acid stimulated oxidation and caused intracellular mitochondrial permeability. Taken together, these present data demonstrated that LPC concentration dependently modulates mitochondrial microenvironment, with low micromolar concentrations of lysophosphatidylcholine sufficient to change hepatic oxidation rate whereas higher concentrations are required to disrupt mitochondrial integrity.