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

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.