FUNCTION OF CARDIOLIPIN PHASE POLYMORPHISM

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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.