Do sterols reduce proton and sodium leaks through lipid bilayers?

Proton and/or sodium electrochemical gradients are critical to energy handl ing at the plasma membranes of all living cells, Sodium gradients are used for animal plasma membranes. all other living organisms use proton gradient s. These chemical and electrical gradients are either created by a cation p umping ATPase or are created by photons or redox, used to make ATP. It has been established that both hydrogen and sodium ions leak through lipid bila yers at approximately the same rate at the concentration they occur in livi ng organisms, Although the gradients are achieved by pumping the cations ou t of the cell. the plasma membrane potential enhances the leakage rate of t hese cations into the cell because of the orientation of the potential. Thi s review proposes that cells use certain lipids to inhibit cation leakage t hrough the membrane bilayers. It assumes that Na+ leaks through the bilayer by a defect mechanism, For Na (+) leakage in animal plasma membranes, the evidence suggests that cholesterol is a key inhibitor of Na (+) leakage. He re I put forth a novel mechanism for proton leakage through lipid bilayers, The mechanism assumes water forms protonated and deprotonated clusters in the lipid bilayer. The model suggests how two features of lipid structures may inhibit Ht leakage, One feature is the fused ring structure of sterols, hopanoids and tetrahymenol which extrude water and therefore clusters from the bilayer, The second feature is lipid structures that crowd the center of the bilayer with hydrocarbon. This can be accomplished either by separat ing the two monolayers with hydrocarbons such as isoprenes or isopranes in the bilayers cleavage plane or by branching the lipid chains in the center of the bilayers with hydrocarbon, The natural distribution of lipids that c ontain these features are examined. Data in the literature shows that plasm a membranes exposed to extreme concentrations of cations are particularly r ich in the lipids containing the predicted qualities. Prokaryote plasma mem branes that reside in extreme acids (acidophiles) contain both hopanoids an d iso/anteiso- terminal lipid branching, Plasma membranes that reside in ex treme base (alkaliphiles) contain both squalene and iso/anteiso- lipids. Th e mole fraction of squalene in alkaliphile bilayers increases. as they are cultured at higher pH. In eukaryotes. cation leak inhibition is here attrib uted to sterols and certain isoprenes, dolichol for lysosomes and peroxysom es. ubiquinone for these in addition to mitochondrion, and plastoquinone fo r the chloroplast, Phytosterols differ from cholesterol because theycontain methyl and ethyl branches on the side chain. The proposal provides a struc ture-function rationale for distinguishing the structures of the phytostero ls as inhibitors of proton leaks from that of cholesterol which is proposed to inhibit leaks of Na+, The most extensively studied of sterols, choleste rol, occurs only in animal cells where there is a sodium gradient across th e plasma membrane. In mammals, nearly 100 proteins participate in cholester ol's biosynthetic and degradation pathway, its regulatory mechanisms and ce ll-delivery system. Although a fat, cholesterol yields no energy on degrada tion. Experiments have shown that it reduces Na (+) and K (+) leakage throu gh lipid bilayers to approximately one third of bilayers that lack the ster ol. If sterols significantly inhibit cation leakage through the lipids of t he plasma membrane, then the general role of all sterols is to save metabol ic ATP energy, which is the penalty for cation leaks into the cytosol. The regulation of cholesterol's appearance in the plasma membrane and the e volution of sterols is discussed in light of this proposed role. (C) 2001 P ublished by Elsevier Science Ltd.