Polyphosphate as a metabolic fuel in Metazoa: A foundational breakthrough invention for biomedical applications

In animals, energy-rich molecules like ATP are generated in the intracellular compartment from metabolites, e.g. glucose, taken up by the cells. Recent results revealed that inorganic polyphosphates (polyP) can provide an extracellular system for energy transport and delivery. These polymers of multiple phosphate units, linked by high-energy phosphoanhydride bonds, use blood platelets as transport vehicles to reach their target cells. In this review it is outlined how polyP affects cell metabolism. It is discussed that polyP influences cell activity in a dual way: (i) as a metabolic fuel transferring metabolic energy through the extracellular space; and (ii) as a signaling molecule that amplifies energy/ATP production in mitochondria. Several metabolic pathways are triggered by polyP, among them biomineralization/hydroxyapatite formation onto bone cells. The accumulation of polyP in the platelets allows long-distance transport of the polymer in the extracellular space. The discovery of polyP as metabolic fuel and signaling molecule initiated the development of novel techniques for encapsulation of polyP into nanoparticles. They facilitate cellular uptake of the polymer by receptor-mediated endocytosis and allow the development of novel strategies for therapy of metabolic diseases associated with deviations in energy metabolism or mitochondrial dysfunctions.