Dataset Information

Cardiolipin-Dependent Properties of Model Mitochondrial Membranes from Molecular Simulations.

ABSTRACT: Cardiolipin is an anionic lipid found in the mitochondrial membranes of eukaryotes ranging from unicellular microorganisms to metazoans. This unique lipid contributes to various mitochondrial functions, including metabolism, mitochondrial membrane fusion and/or fission dynamics, and apoptosis. However, differences in cardiolipin content between the two mitochondrial membranes, as well as dynamic fluctuations in cardiolipin content in response to stimuli and cellular signaling events, raise questions about how cardiolipin concentration affects mitochondrial membrane structure and dynamics. Although cardiolipin's structural and dynamic roles have been extensively studied in binary mixtures with other phospholipids, the biophysical properties of cardiolipin in higher number lipid mixtures are still not well resolved. Here, we used molecular dynamics simulations to investigate the cardiolipin-dependent properties of ternary lipid bilayer systems that mimic the major components of mitochondrial membranes. We found that changes to cardiolipin concentration only resulted in minor changes to bilayer structural features but that the lipid diffusion was significantly affected by those alterations. We also found that cardiolipin position along the bilayer surfaces correlated to negative curvature deflections, consistent with the induction of negative curvature stress in the membrane monolayers. This work contributes to a foundational understanding of the role of cardiolipin in altering the properties in ternary lipid mixtures composed of the major mitochondrial phospholipids, providing much-needed insights to help understand how cardiolipin concentration modulates the biophysical properties of mitochondrial membranes.

SUBMITTER: Wilson BA

PROVIDER: S-EPMC6697365 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Cardiolipin-Dependent Properties of Model Mitochondrial Membranes from Molecular Simulations.

Wilson Blake A BA Ramanathan Arvind A Lopez Carlos F CF

Biophysical journal 20190702 3

Cardiolipin is an anionic lipid found in the mitochondrial membranes of eukaryotes ranging from unicellular microorganisms to metazoans. This unique lipid contributes to various mitochondrial functions, including metabolism, mitochondrial membrane fusion and/or fission dynamics, and apoptosis. However, differences in cardiolipin content between the two mitochondrial membranes, as well as dynamic fluctuations in cardiolipin content in response to stimuli and cellular signaling events, raise quest ...[more]

PMID: 31349988

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Project description:The anionic phospholipid cardiolipin has an unusual dimeric structure with a two-phosphate headgroup and four acyl chains. Cardiolipin is present in energy-transducing membranes that maintain electrochemical gradients, including most bacterial plasma membranes and the mitochondrial inner membrane, where it mediates respiratory complex assembly and activation, among many other roles. Dysfunctional biogenesis of cardiolipin is implicated in the pathogenesis of several diseases including Barth syndrome. Because cardiolipin is a dominant anionic lipid in energy-conserving membranes, its headgroup is a major contributor to surface charge density and the bilayer electrostatic profile. However, the proton dissociation behavior of its headgroup remains controversial. In one model, the pKa values of the phosphates differ by several units and the headgroup exists as a monoanion at physiological pH. In another model, both phosphates ionize as strong acids with low pKa values and the headgroup exists in dianionic form at physiological pH. Using independent electrokinetic and spectroscopic approaches, coupled with analysis using Gouy-Chapman-Stern formalism, we have analyzed the ionization properties of cardiolipin within biologically relevant lipid bilayer model systems. We show that both phosphates of the cardiolipin headgroup show strong ionization behavior with low pKa values. Moreover, cardiolipin variants lacking structural features proposed to be required to maintain disparate pKa values--namely the secondary hydroxyl on the central glycerol or a full complement of four acyl chains--were shown to have ionization behavior identical to intact cardiolipin. Hence, these results indicate that within the physiological pH range, the cardiolipin headgroup is fully ionized as a dianion. We discuss the implications of these results with respect to the role of cardiolipin in defining membrane surface potential, activating respiratory complexes, and modulating membrane curvature.

Project description:Plants synthesize small molecule diterpenes composed of 20 carbons from precursor isopentenyl diphosphate and dimethylallyl disphosphate, manufacturing diverse compounds used for defense, signaling, and other functions. Industrially, diterpenes are used as natural aromas and flavoring, as pharmaceuticals, and as natural insecticides or repellents. Despite diterpene ubiquity in plant systems, it remains unknown how plants control diterpene localization and transport. For many other small molecules, plant cells maintain transport proteins that control compound compartmentalization. However, for most diterpene compounds, specific transport proteins have not been identified, and so it has been hypothesized that diterpenes may cross biological membranes passively. Through molecular simulation, we study membrane transport for three complex diterpenes from among the many made by members of the Lamiaceae family to determine their permeability coefficient across plasma membrane models. To facilitate accurate simulation, the intermolecular interactions for leubethanol, abietic acid, and sclareol were parametrized through the standard CHARMM methodology for incorporation into molecular simulations. To evaluate the effect of membrane composition on permeability, we simulate the three diterpenes in two membrane models derived from sorghum and yeast lipidomics data. We track permeation events within our unbiased simulations, and compare implied permeation coefficients with those calculated from Replica Exchange Umbrella Sampling calculations using the inhomogeneous solubility diffusion model. The diterpenes are observed to permeate freely through these membranes, indicating that a transport protein may not be needed to export these small molecules from plant cells. Moreover, the permeability is observed to be greater for plant-like membrane compositions when compared against animal-like membrane models. Increased permeability for diterpene molecules in plant membranes suggest that plants have tailored their membranes to facilitate low-energy transport processes for signaling molecules.

Dataset Information

Cardiolipin-Dependent Properties of Model Mitochondrial Membranes from Molecular Simulations.

Publications

Cardiolipin-Dependent Properties of Model Mitochondrial Membranes from Molecular Simulations.

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