Phosphate homeostasis and energy metabolism in eukaryotes
My interest for phosphate homeostasis and the function of highly phosphorylated molecules (inositol polyphosphate and inorganic polyphosphate) started during my first postdoc when I was working on membrane trafficking at the University of Lausanne (Switzerland)(see below). I then decided to move to a lab with theoretical and experimental expertise in phosphate homeostasis and energy metabolism. I am now working in the lab of Adolfo Saiardi at University College London (MRC LMCB).
My research brings together metabolism and signalling and focuses on how eukaryotic cells sense intracellular phosphate, how they deal with phosphate stores, and how they regulate the size of the different phosphate pools (inositol polyphosphate, inorganic polyphosphate, nucleotides pool, free phosphate). I am using two model systems to tackle the problem: yeast (Saccharomyces cerevisiae, Schizosaccharomyces pombe) and the social amoeba Dictyostelium discoideum.
What are phosphate homeostasis and energy metabolism?
Phosphate homeostasis defines how cells and organisms control the uptake, the storage, and the export of phosphate to maintain a suitable phosphate concentration. What is a suitable concentration? Intracellular phosphate concentration has not been precisely determined. However, one can expect that it must be high enough to satisfy the requirements imposed by the high turnover rate of ATP, the main currency in the cells. In bacteria for instance, the renewal of the entire ATP pool has been shown to occur 100-250 times per minute. This means that as many phosphate molecules are required to produce ATP and to keep ATP concentration constant. One can also predict that intracellular phosphate levels cannot be too high. Phosphate is a product of many reversible biochemical reactions. As such, a high concentration of phosphate would inhibit those reactions.
So far, no intracellular phosphate sensing machinery has been identified although several reports and my recent data suggest the existence of such a sensor.
“Energy metabolism is the process of generating energy (ATP) from nutrients” (source). On the opposite to inorganic phosphate, ATP concentration is tightly regulated. It is between 1-2 mM in the budding yeast and 4-5 mM in mammalian cells. There is an obvious structural relationships between phosphate and ATP since ATP contains three phosphate moieties. Therefore, phosphate homeosatis and energy metabolism are intrinsically connected.
Phosphate homeostasis and membrane dynamics
In yeast, phosphate is stored as a polymer called polyphosphate (polyP), in the lumen of vacuoles. The enzyme responsible for the synthesis and translocation of polyP is the Vacuole Transporter Chaperone complex (VTC complex). The accumulation and mobilization of phosphate is regulated by a number of proteins. Interestingly many of the the proteins involved in phosphate homeostasis are also required for proper vacuole fusion/fission dynamics.
Recently, the role of inositol pyrophosphates in the control of polyP synthesis has been described. These small compounds are involved in a large number of cellular processes including membrane trafficking. For instance, the synthesis of inositol pyrophosphates is required for normal vacuole morphology. I am currently investigating how these small compounds may affect vacuole membrane dynamics in vivo and in vitro.