The Saiardi lab is interested in the intersection between signalling and basic metabolism. Specifically we study the role played by inositol pyrophosphates in maintaining cell homeostasis. Inositol pyrophosphates are present in all eukaryotic cells and belong to the inositol phosphates family of soluble signalling molecules. Both inositol phosphates and inositol pyrophosphates are obtained by the combinatorial attachment of phosphate groups to inositol. However, the inositol pyrophosphates are distinguished by their one or more high-energy phosphoanhydride bonds (pyro- moieties). The energy stored in these bonds provides the inositol pyrophosphates with the potential to take part in new and not yet fully understood molecular actions. The structure of these molecules and their conservation in eukaryotic biology suggests a fundamental signalling role, acting through a unique mechanism.
Alteration of inositol pyrophosphate levels has been associated with a wide collection of phenotypes as well as important human pathology such as obesity, diabetes and cancer. These pleiotropic effects suggest an ability to control a central cellular function. Our finding that inositol pyrophosphates regulate intracellular levels of ATP places these molecules at the interface between signalling and basic metabolism.
We have developed three model systems with altered inositol polyphosphate metabolism: the yeast Saccharomyces cerevisiae; the amoeba Dictyostelium discoideum; and a number of CRISPR-generated mammalian cell lines. Each model allows us to investigate different aspects of inositol pyrophosphate biology. We also endeavour to develop new technologies for studying inositol pyrophosphate signalling. Our success so far in designing novel methodologies has opened new research avenues in the field and drawn further attention to these molecules. We are currently directing our efforts towards developing techniques to allow localisation of inositol pyrophosphates in cells. To achieve this important goal, the lab is interested in the development of new probes and imaging technologies such as Raman spectromicroscopy and multi-isotope imaging mass spectrometry (MIMS).
In our quest to understand how inositol pyrophosphates regulate basic metabolism, we are studying inorganic polyphosphate (polyP) biology. The phosphate chain of polyP represents one of the simplest biological polymers but it is also one of the least characterized. While many specific signalling functions have been attributed to this ubiquitous polymer, intrinsic to polyP’s structure is a fundamental role as cellular free phosphate (Pi) buffer. In yeast, inositol pyrophosphates regulate the cellular levels of polyP. We aim to extend these observations since phosphate homeostasis is essential to cellular wellbeing. Understanding the metabolic link between inositol pyrophosphates and polyP will help to elucidate how inositol pyrophosphates regulate cellular metabolism. Additionally, our discovery of a new protein post-translational modification consisting of the covalent attachment of polyP to lysine residues (protein polyphosphorylation) has intensified interest in polyP, offering a possible mechanism for the range of cellular functions attributed to them.
Further to our primary focus investigating the role played by inositol pyrophosphate in today’s cells, we also pursue an academic interest in understanding how an ancient inositol phosphate module with limited functions has evolved to become the sophisticated system of signalling molecules present in our cells. Similarly, we are curious how and why polyP, an ancient molecule that may have preceded ATP as the primary energy source driving prebiotic reactions, has been retained by evolution and is still utilised in many modern cellular processes.
The laboratory is collegial and very cooperative. We are always open to new collaborations aimed at elucidating the multifaceted aspects of inositol pyrophosphate and inorganic polyphosphate signalling.