title: Distinct membrane properties are differentially influenced by cardiolipin content and acyl chain composition in biomimetic membranes.
abstract: Cardiolipin (CL) has a critical role in maintaining mitochondrial inner membrane structure. In several conditions such as heart failure and aging, there is loss of CL content and remodeling of CL acyl chains, which are hypothesized to impair mitochondrial inner membrane biophysical organization. Therefore, this study discriminated how CL content and acyl chain composition influenced select properties of simple and complex mitochondrial mimicking model membranes. We focused on monolayer excess area/molecule (a measure of lipid miscibility), bilayer phase transitions, and microdomain organization. In monolayer compression studies, loss of tetralinoleoyl [(18:2)4] CL content decreased the excess area/molecule. Replacement of (18:2)4CL acyl chains with tetraoleoyl [(18:1)4] CL or tetradocosahexaenoyl [(22:6)4] CL generally had little influence on monolayer excess area/molecule; in contrast, replacement of (18:2)4CL acyl chains with tetramyristoyl [(14:0)4] CL increased monolayer excess area/molecule. In bilayers, calorimetric studies showed that substitution of (18:2)4CL with (18:1)4CL or (22:6)4CL lowered the phase transition temperature of phosphatidylcholine vesicles whereas (14:0)4CL had no effect. Finally, quantitative imaging of giant unilamellar vesicles revealed differential effects of CL content and acyl chain composition on microdomain organization, visualized with the fluorescent probe Texas Red DHPE. Notably, microdomain areas were decreased by differing magnitudes upon lowering of (18:2)4CL content and substitution of (18:2)4CL with (14:0)4CL or (22:6)4CL. Conversely, exchanging (18:2)4CL with (18:1)4CL increased microdomain area. Altogether, these data demonstrate that CL content and fatty acyl composition differentially target membrane physical properties, which has implications for understanding how CL regulates mitochondrial activity and the design of CL-specific therapeutics.
authors.affiliation: Department of Biochemistry & Molecular Biology, USA; East Carolina Diabetes & Obesity Institute, Brody School of Medicine, East Carolina University, 115 Heart Drive, Mail Stop 743, Greenville, NC 27834, USA.
authors.forename: Edward Ross
authors.initials: ER
authors.lastname: Pennington
authors.affiliation: Department of Biochemistry & Molecular Biology, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Fix
authors.affiliation: Department of Biochemistry & Molecular Biology, USA; East Carolina Diabetes & Obesity Institute, Brody School of Medicine, East Carolina University, 115 Heart Drive, Mail Stop 743, Greenville, NC 27834, USA.
authors.forename: E Madison
authors.initials: EM
authors.lastname: Sullivan
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Virginia Tech Corporate Research Center, 1035 ILSB, 1981 Kraft Drive, Blacksburg, VA 24060, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Brown
authors.affiliation: Department of Chemistry, East 10th Street, Mail Stop 552, East Carolina University, Greenville, NC 27854, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Kennedy
authors.affiliation: Department of Biochemistry & Molecular Biology, USA; East Carolina Diabetes & Obesity Institute, Brody School of Medicine, East Carolina University, 115 Heart Drive, Mail Stop 743, Greenville, NC 27834, USA. Electronic address: shaikhsa@ecu.edu.
authors.forename: Saame Raza
authors.initials: SR
authors.lastname: Shaikh
mesh_terms: D000818:Animals; D032701:Biomimetics / Q000379:methods; D002308:Cardiolipins / Q000378:metabolism*; D002417:Cattle; D008051:Lipid Bilayers / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D008566:Membranes / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism*; D010713:Phosphatidylcholines / Q000378:metabolism; D044366:Transition Temperature; D053835:Unilamellar Liposomes / Q000378:metabolism
chemical_list: D002308:Cardiolipins; D008051:Lipid Bilayers; D010713:Phosphatidylcholines; D053835:Unilamellar Liposomes
keywords: Cardiolipin; Docosahexaenoic acid; Mitochondria; Monolayers; Pressure-area isotherms