Phosphate Homeostasis − A Vital Metabolic Equilibrium Maintained Through the INPHORS Signaling Pathway

Abstract

Cells face major changes in demand for and supply of inorganic phosphate (P i ). P i is often a limiting nutrient in the environment, particularly for plants and microorganisms. At the same time, the need for phosphate varies, establishing conflicts of goals. Cells experience strong peaks of P i demand, e.g., during the S-phase, when DNA, a highly abundant and phosphate-rich compound, is duplicated. While cells must satisfy these P i demands, they must safeguard themselves against an excess of P i in the cytosol. This is necessary because P i is a product of all nucleotide-hydrolyzing reactions. An accumulation of P i shifts the equilibria of these reactions and reduces the free energy that they can provide to drive endergonic metabolic reactions. Thus, while P i starvation may simply retard growth and division, an elevated cytosolic P i concentration is potentially dangerous for cells because it might stall metabolism. Accordingly, the consequences of perturbed cellular P i homeostasis are severe. In eukaryotes, they range from lethality in microorganisms such as yeast ( Sethuraman et al., 2001 ; Hürlimann, 2009 ), severe growth retardation and dwarfism in plants ( Puga et al., 2014 ; Liu et al., 2015 ; Wild et al., 2016 ) to neurodegeneration or renal Fanconi syndrome in humans ( Legati et al., 2015 ; Ansermet et al., 2017 ). Intracellular P i homeostasis is thus not only a fundamental topic of cell biology but also of growing interest for medicine and agriculture.

Phosphate Restriction Promotes Longevity via Activation of Autophagy and the Multivesicular Body Pathway

“…Cells store phosphate in the form of polyP, a linear polymer of tens to hundreds of P i residues that preferentially accumulates in acidocalcisomes, organelles that are ubiquitous in nature [21]. In yeast cells, the vacuole represents the acidocalcisome-like compartment, accumulating polyP that can account for almost a quarter of their dry weight [42]. The concentration of cellular polyP fluctuates with the availability of phosphate, and polyP granules, formed under high phosphate conditions, serve as energy source and reservoir of P i [20,21,43].…”

Cell-to-cell heterogeneity of phosphate gene expression in yeast is controlled by alternative transcription, 14-3-3 and Spl2

“…In S. cerevisiae phosphate homeostasis is regulated by an interplay between low and high affinity phosphate transporters allowing survival at different environmental phosphate concentrations; for review see [3][4][5]7]. Expression of these transporters at different phosphate concentrations is regulated by a complex network with a major role for the transcription factor Pho4.…”

“…In S. cerevisiae phosphate homeostasis is a tightly regulated process; for review see [4][5][6][7]. When phosphate is abundant the low affinity transporters Pho87 and Pho90 are responsible for phosphate uptake [4,8].…”

Cycles, sources, and sinks: Conceptualizing how phosphate balance modulates carbon flux using yeast metabolic networks

“…A related, predictive case can be made for glycerol, which is synthesized during the lower arm of glycolysis and is accompanied by the release of Pi. Glycerol biosynthesis from dihydroxyacetone phosphate (DHAP) occurs in two steps, where the first step results in the synthesis of glycerol-3-phosphate (catalyzed by Gpd1 and Gpd2), and the second step results in the synthesis of glycerol and the release of one Pi molecule by the action of glycerol-3-phosphatases (Hor2 and Rhr2) ( Austin and Mayer, 2020 ; Figure 3C ). In line with the role of glycerol as a phosphate source, glycerol levels are elevated in response to phosphate limitation ( Kazemi Seresht et al, 2011 ).…”

“…These opposing substrate cycles, and the relative activity of phosphorylation/dephosphorylation, determine how much nucleoside monophosphates (and eventually triphosphates) are present, or if they will be converted to nucleosides. A more recent review points to the fact that upon extreme Pi starvation, as a ‘last resort’ cells induce enzymes that release Pi from nucleotides, since it would otherwise be illogical for cells to deplete its pools of nucleotides, which are critical for future cell division ( Austin and Mayer, 2020 ). These points are all entirely consistent with nucleotides (and NAD related molecules) being Pi sinks, which will serve to eventually release Pi if phosphate levels within cells are not restored.…”