FUNCTION OF CARDIOLIPIN PHASE POLYMORPHISM

心磷脂相多态性的功能

• 批准号: 3354278
• 负责人: GARY L POWELL
• 金额: $ 13.9万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-04-01 至 1995-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3354278
• 关键词: X ray crystallography; adenosine triphosphate; adenosinetriphosphatase; affinity chromatography; cardiolipins; cell death; cytochrome oxidase; freeze etching; hydrogen; ion transport; lipid structure; liposomes; membrane activity; membrane lipids; membrane model; membrane permeability; membrane potentials; membrane transport proteins; mitochondrial membrane; nuclear magnetic resonance spectroscopy; phase change; phosphatidylcholines

A basic function of a biological membrane is to provide a barrier between cellular compartments. For the inner mitochondrial membrane, low permeability to protons seems particularly crucial because the proton gradient across this membrane drives the synthesis of ATP in mitochondria. Direct measurement of the proton permeability using lipid vesicles in which pyranine, a fluorescent pH indicator, has been trapped, and analysis of the digitized rates provides values of 3-4 x 10-3 cm/sec, much larger values that the permeability, because of the low concentration of protons at physiological pH, and possible special strategies, the actual passive mitochondrial proton flux in vivo must be more than adequately matched by adequate proton pumping rates by the electron transport system. Cardiolipin or diphosphatidylglycerol is a unique phospholipid localized almost exclusively to the mitochondrion. The molecular exhibits a strong affinity for the surface of intrinsic membrane proteins like cytochrome c oxidase is shown using spin-labeled cardiolipin analogues and 31P-NMR. This lipid also exhibits phase polymorphism, as measured in bulk using 31P- NMR and low angle X-ray diffraction, converting from lamellar phase to the inverted hexagonal phase when the salt concentration is raised above 1.5M. This phase polymorphism has been shown, using cardiolipin analogues with differing numbers of fatty acyl chains, to be a function of the shape of the molecule. While increasing evidence rules out the formation of non- lamellar phases in vivo, the shape of this molecule, together with its unusual affinity for intrinsic membrane proteins, points toward a unique function for cardiolipin sealing the irregular surface of these system of proteoliposomes composed of diphosphatidylcholine and cytochrome oxidase with and without cardiolipin. Comparison of the proton permeabilities of these two types of vesicles should provide evidence for or against the hypothesis that cardiolipin prevent proton or other ion leaks through the interface between the bilayer and the protein surface. In heart tissue, lysophospholipids and free fatty acids formed during myocardial infarct probably increase the proton permeability of mitochondria, uncoupling electron transport, and limiting ATP synthesis, directly resulting in cell death. Demonstration of this molecular basis of cell death would enable better intervention and treatment of patients with heart disease.

生物膜的基本功能是在生物膜之间提供屏障。 细胞间室 对于线粒体内膜， 质子的渗透性似乎特别重要，因为质子 跨膜的梯度驱动线粒体中ATP的合成。 使用脂质囊泡直接测量质子渗透性，其中 荧光pH指示剂pyranine被捕获， 数字化速率提供3-4 x 10-3 cm/sec的值，更大的值 由于质子浓度低， 生理pH值，和可能的特殊策略，实际被动 体内线粒体质子通量必须比适当匹配， 通过电子传输系统的足够的质子泵送速率。 心磷脂或二磷脂酰甘油是一种独特的磷脂定位 几乎只属于北卡罗来纳州。 该分子表现出强烈的 对细胞色素c等内在膜蛋白表面的亲和力 使用自旋标记的心磷脂类似物和31 P-NMR显示氧化酶。 这种脂质也表现出相位多态性，如使用31 P- NMR和低角X射线衍射，从层状相转化为 当盐浓度升高到1.5M以上时，形成了反六方相。 使用心磷脂类似物， 不同数量的脂肪酰基链，是形状的函数， 分子。 虽然越来越多的证据排除了非- 层状相在体内，这种分子的形状，连同其 不寻常的亲和力内在膜蛋白，指向一个独特的 心磷脂密封这些系统的不规则表面的功能 由二磷脂酰胆碱和细胞色素氧化酶组成的脂蛋白体 加和不加心磷脂。 质子渗透率的比较 这两种类型的囊泡应该提供证据支持或反对 假设心磷脂防止质子或其它离子通过 双层和蛋白质表面之间的界面。 在心脏组织中，溶血磷脂和游离脂肪酸在 心肌梗死可能增加质子渗透性 线粒体、解偶联电子传递和限制ATP合成， 直接导致细胞死亡。 这种分子基础的证明 细胞死亡将使更好的干预和治疗患者， 心脏病