Role of Polyphosphate in Mitochondria: From Modification of Energy Metabolism to Induction of the Cell Death

Abstract

Inorganic polyphosphate (polyP) is found in all living organisms ranging from bacteria to mammals. PolyP plays multiple physiological functions, which are distinct and dependent on the type of organism and the subcellular localization of the polymer. Recently we demonstrated that polyP levels are dependent on the cell metabolism and can be changed by mitochondrial substrates and inhibitors. We propose the existence of a feedback mechanism where polyP production and cell energy metabolism regulate each other. In order to investigate this we study the effect of polyP on mitochondrial oxygen consumption. We have found that application of short polyP (14 phosphate residues) or medium polyP (70 ortophosphates) significantly increase the level of respiratory coefficient by activation of state V3 and inhibition of V4 compare to control. Importantly, both short and medium polyP significantly reduced efficiency of oxidative phosphorylation (ADP/O ratio). It has previously been reported that polyP can modify membrane permeability for ions that can be a trigger for changes in mitochondrial metabolism. Furthermore polyP has been linked to activation of the mitochondrial permeability transition pore (mPTP) in different cells that also can be activated by calcium. Long, medium, and in lower degree, short polyP increase permeability of de-energised mitochondria for Ca2+. This effect was dependent on inhibitor of mPTP - cyclosporine A. We also found that long polyP (130 orthophosphates) caused cell death in primary neurons and astrocytes, while medium (70) polyP had a much smaller effect and short (14) did not cause any. Thus, polyP has a multiple action on mitochondrial function from modification of mitochondrial energy metabolism to stimulation of calcium permeability and cell death.