title: Micromolar changes in lysophosphatidylcholine concentration cause minor effects on mitochondrial permeability but major alterations in function.
abstract: 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 40-200μM lysophosphatidylcholine caused cyclosporine A-resistant swelling in a concentration-dependent manner. However, when mitochondria were challenged with 220μM CaCl2, cyclosporine A protected against permeability transition induced by 40μM, but not 80μM lysophosphatidylcholine. Incubation with 40-120μM lysophosphatidylcholine also increased mitochondrial permeability to 75μM CaCl2 in a concentration-dependent manner. Interestingly, despite incubation with 80μM 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 100μM lysophosphatidylcholine. Finally, while 40μM lysophosphatidylcholine has no effect on fatty acid oxidation and mitochondria remained impermeable in intact hepatocytes, 100μM 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.
authors: Department of Pathology and Laboratory Medicine, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors: Norris I
authors: NI
authors: Hollie
authors: Department of Pathology and Laboratory Medicine, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors: James G
authors: JG
authors: Cash
authors: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors: M Abdul
authors: MA
authors: Matlib
authors: Department of Internal Medicine, Division of Endocrinology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors: Matthew
authors: M
authors: Wortman
authors: Department of Pathology and Laboratory Medicine, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors: Joshua E
authors: JE
authors: Basford
authors: Department of Pathology and Laboratory Medicine, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors: William
authors: W
authors: Abplanalp
authors: Department of Pathology and Laboratory Medicine, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, OH, USA. Electronic address: huidy@ucmail.uc.edu.
authors: David Y
authors: DY
authors: Hui
mesh_terms: D000818:Animals; D002122:Calcium Chloride / Q000008:administration & dosage; D016572:Cyclosporine / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D054513:Group IV Phospholipases A2 / Q000172:deficiency / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008244:Lysophosphatidylcholines / Q000008:administration & dosage* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects*; D010539:Permeability / Q000187:drug effects*
chemical_list: D008244:Lysophosphatidylcholines; D016572:Cyclosporine; D054513:Group IV Phospholipases A2; D002122:Calcium Chloride
keywords: Hepatocyte; Lysophosphatidylcholine; Mitochondrion; Oxidation