Abstract
Mammalian cells maintain the complex glycerophospholipid (GPL) class compositions of their various membranes within close limits because this is essential to their well‐being or viability. Surprisingly, however, it is still not understood how those compositions are maintained except that GPL synthesis and degradation are closely coordinated. Here, we hypothesize that abrupt changes in the chemical activity of the individual GPL classes coordinate synthesis and degradation as well other the homeostatic processes. We have previously proposed that only a limited number of “allowed” or “optimal” GPL class compositions exist in cellular membranes because those compositions are energetically more favorable than others, that is, they represent local free energy minima (Somerharju et al 2009, Biochim. Biophys. Acta 1788, 12‐23). This model, however, could not satisfactorily explain how the “optimal” compositions are sensed by the key homeostatic enzymes, that is, rate‐limiting synthetizing enzymes and homeostatic phospholipases. We now hypothesize that when the mole fraction of a GPL class exceeds an optimal value, its chemical activity abruptly increases which (a) increases its propensity to efflux from the membrane thus making it susceptible for hydrolysis by homeostatic phospholipases; (b) increases its potency to inhibit its own biosynthesis via a feedback mechanism; (c) enhances its conversion to another glycerophospholipid class via a novel process termed “head group remodeling” or (d) enhances its translocation to other subcellular membranes. In summary, abrupt change in the chemical activity of the individual GPL classes is proposed to regulate and coordinate those four processes maintaining GPL class homeostasis in mammalian cells.
Highlights
Glycerophospholipids (GPLs) are the most abundant lipids in virtually all mammalian membranes each of which contain more than 10 GPL classes varying in the structure of the polar head group
When the mole fraction of an GPL class exceeds that in an optimal composition, its chemical activity abruptly increases, which (i) increases its propensity to efflux from the membranes making it susceptible for hydrolysis by homeostatic phospholipases; (ii) increases its potency to inhibit its own biosynthesis via a feedback mechanism; (iii) enhances its conversion to another GPL class via “head group remodeling” or (iv) enhances its translocation to another membrane
Despite the vital importance of such GPL homeostasis, information regarding the mechanisms underlying this crucial phenomenon in mammalian cells is limited
Summary
Glycerophospholipids (GPLs) are the most abundant lipids in virtually all mammalian membranes each of which contain more than 10 GPL classes varying in the structure of the polar head group. On the other hand, when the synthesis of PC, PE or PS was inhibited, their turnover decreased correspondingly (Fullerton and Bakovic, 2010; Fullerton et al, 2009; Nishijima et al, 1984; Polokoff et al, 1981; Steenbergen et al, 2006) There it is no information on how the coordination of synthesis and degradation is accomplished mechanistically, which must be a challenging task (Fig. 1) due to the presence of many GPL classes. We present the so-called Optimal Composition Model (OCmodel) which appears to represent the first attempt to explain how synthesis and degradation of GPLs could be accurately coordinated This hypothesis was inspired by our recent findings on the processes involved in GPL homeostasis in mammalian cells
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