Added publication Inorganic polyphosphate (polyP) is an ancestral, ubiquitous, and well-conserved polymer, which is present in all the studied organisms. It is formed by individual subunits of orthophosphate which are linked together by bonds structurally similar and isoenergetic to those found in ATP. While the metabolism and the physiological roles of polyP in some organisms, including bacteria and yeast, have already been described, the exact role of this polymer in mammalian physiology remains still poorly explored. In these organisms, polyP shows a co-localization with mitochondria. Accordingly, its role as a key regulator of bioenergetics has already been demonstrated by our group and others. Here, using Wild-type (Wt) and MitoPPX (cells enzymatically depleted of mitochondrial polyP) SH-SY5Y cells, we conducted a comprehensive study of the status of cellular physiology, using proteomics and metabolomics approaches. Our results suggested a clear dysregulation of mitochondrial physiology, especially of bioenergetics, in MitoPPX cells when compared with Wt. Interestingly, the effects induced by the enzymatically depletion of polyP are similar to those present in the mitochondrial dysfunction which is observed in neurodegenerative disorders and in neuronal aging. In fact, the role of polyP as a component of the cellular stress responses has already been proposed in diverse organisms, including mammals. Thereafter, our data could contribute to place the metabolism of mitochondrial polyP as a valid and innovative pharmacological target in these conditions.