Abstract: Since the early stages of life on earth, cellular metabolism has evolved to adapt to fluctuations in nutrient and oxygen availability. In this context, mammals, which are probably the organisms that show one of the highest levels of metabolic complexity, have developed an elegant system that uses constant and rechargeable energy sources of modulate their metabolism. This homeostasis is especially important in the central nervous system, as neurons and other cells in the brain are highly susceptible to fluctuations in nutrients and oxygen availability. At the molecular level, these energy sources are based on molecules that contain highly energetic bonds. The main metabolite with energy-rich bonds in mammalian cells is adenosine triphosphate. However, other molecules also present dynamic roles in cellular metabolism in these organisms. One of the lesser known of these molecules is inorganic polyphosphate (polyP). PolyP is an ancient polymer, which has been well conserved throughout evolution; it is present in every tissue of all studied organisms. PolyP bonds are isoenergetic to those found in adenosine triphosphate, and its role as a key energy metabolite has already been demonstrated by us and others in various systems, including mammalian cells (Guitart-Mampel et al., 2022). PolyP is ubiquitously distributed in the cell, although one of its preferred locations in mammals is mitochondria, where the vast majority of adenosine triphosphate is produced via oxidative phosphorylation. In fact, the levels of mitochondrial polyP seem to be intimately related to the status of the electron transfer chain. Moreover, the regulatory effects of polyP on some crucial mammalian mitochondrial processes that are closely related to the bioenergetic status of cells and usually deleteriously affected in neurological disorders; such as calcium and protein homeostasis, and the maintenance of the oxidative status; have also been described. Most likely as a consequence of its role in bioenergetics, polyP has also been reported to be involved in the cellular stress response of various organisms. For example, it has been shown that polyP can act as a primordial chaperone (Gray et al., 2014). This stress response is also often activated in neurological disorders. In fact, a recent and elegant study proposed that assessing the levels of polyP released by astrocytes could serve as a promising biomarker in amyotrophic lateral sclerosis and frontotemporal dementia (Arredondo et al., 2022). However, the molecular mechanism by which polyP exerts its effects on mitochondrial and cellular physiology, including bioenergetics, remains poorly understood, especially in mammals. One plausible explanation for these effects could be via the signaling role that polyP has shown in different organisms, including mammalian cells.