Hypothesis: Chemical activity regulates and coordinates the processes maintaining glycerophospholipid homeostasis in mammalian cells

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.

Active cholesterol 20 years on

“…By analogy with active cholesterol, a recent proposal suggested that the homeostasis of membrane glycerophospholipids is controlled by their chemical activity 66 . According to this hypothesis, the accessibility of an excess of phospholipid is sensed by regulatory proteins that mediate feedback responses.…”

A Novel Process Maintaining Glycerophospholipid Homeostasis in Mammalian Cells

“…Finally, we note that, beside the acute regulation discussed above there are also other, slower processes regulating GPL composition of mammalian cells operating under particular cellular states such as mitosis, differentiation and apoptosis (41).…”

“…Because of all those four processes can influence GPL composition and because there are so many GPL classes present in each membrane, it must be highly challenging to maintain GPL homeostasis in a membrane, i.e., it requires strict coordination of biosynthesis, degradation, head group remodeling and inter-organelle translocation. To date, the mechanism(s) underlying such coordination have not been uncovered, but we have recently hypothesized that the key coordinating factor is the chemical activity of the different GPL classes (41). According this hypothesis, abrupt composition-dependent changes in the chemical activity (≈ mole fraction) of the individual GPLs regulate all four homeostatic processes thus coordinating them to maintain homeostasis.…”