Inorganic polyphosphate and the regulation of mitochondrial physiology

Inorganic polyphosphate (polyP) is an ancient polymer that is well-conserved throughout evolution. It is formed by multiple subunits of orthophosphates linked together by phosphoanhydride bonds. The presence of these bonds, which are structurally similar to those found in ATP, and the high abundance of polyP in mammalian mitochondria, suggest that polyP could be involved in the regulation of the physiology of the organelle, especially in the energy metabolism. In fact, the scientific literature shows an unequivocal role for polyP not only in directly regulating oxidative a phosphorylation; but also in the regulation of reactive oxygen species metabolism, mitochondrial free calcium homeostasis, and the formation and opening of mitochondrial permeability transitions pore. All these processes are closely interconnected with the status of mitochondrial bioenergetics and therefore play a crucial role in maintaining mitochondrial and cell physiology. In this invited review, we discuss the main scientific literature regarding the regulatory role of polyP in mammalian mitochondrial physiology, placing a particular emphasis on its impact on energy metabolism. Although the effects of polyP on the physiology of the organelle are evident; numerous aspects, particularly within mammalian cells, remain unclear and require further investigation. These aspects encompass, for example, advancing the development of more precise analytical methods, unraveling the mechanism responsible for sensing polyP levels, and understanding the exact molecular mechanism that underlies the effects of polyP on mitochondrial physiology. By increasing our understanding of the biology of this ancient and understudied polymer, we could unravel new pharmacological targets in diseases where mitochondrial dysfunction, including energy metabolism dysregulation, has been broadly described.