Inorganic Polyphosphate, Mitochondria, and Neurodegeneration

Abstract

With an aging population, the presence of aging-associated pathologies is expected to increase within the next decades. Regrettably, we still do not have any valid pharmacological or non-pharmacological tools to prevent, revert, or cure these pathologies. The absence of therapeutical approaches against aging-associated pathologies can be at least partially explained by the relatively lack of knowledge that we still have regarding the molecular mechanisms underlying them, as well as by the complexity of their etiopathology. In fact, a complex number of changes in the physiological function of the cell has been described in all these aging-associated pathologies, including neurodegenerative disorders. Based on multiple scientific manuscripts produced by us and others, it seems clear that mitochondria are dysfunctional in many of these aging-associated pathologies. For example, mitochondrial dysfunction is an early event in the etiopathology of all the main neurodegenerative disorders, and it could be a trigger of many of the other deleterious changes which are present at the cellular level in these pathologies. While mitochondria are complex organelles and their regulation is still not yet entirely understood, inorganic polyphosphate (polyP) could play a crucial role in the regulation of some mitochondrial processes, which are dysfunctional in neurodegeneration. PolyP is a well-preserved biopolymer; it has been identified in every organism that has been studied. It is constituted by a series of orthophosphates connected by highly energetic phosphoanhydride bonds, comparable to those found in ATP. The literature suggests that the role of polyP in maintaining mitochondrial physiology might be related, at least partially, to its effects as a key regulator of cellular bioenergetics. However, further research needs to be conducted to fully elucidate the molecular mechanisms underlying the effects of polyP in the regulation of mitochondrial physiology in aging-associated pathologies, including neurodegenerative disorders. With a significant lack of therapeutic options for the prevention and/or treatment of neurodegeneration, the search for new pharmacological tools against these conditions has been continuous in past decades, even though very few therapeutic approaches have shown potential in treating these pathologies. Therefore, increasing our knowledge about the molecular mechanisms underlying the effects of polyP in mitochondrial physiology as well as its metabolism could place this polymer as a promising and innovative pharmacological target not only in neurodegeneration, but also in a wide range of aging-associated pathologies and conditions where mitochondrial dysfunction has been described as a crucial component of its etiopathology, such as diabetes, musculoskeletal disorders, and cardiovascular disorders.

Keywords: Aging; Bioenergetics; Inorganic polyphosphate; Mitochondrial dysfunction; Mitochondrial permeability transition pore; Mitochondrial unfolded protein response; Neurodegeneration; Oxidative phosphorylation; PolyP; Stress response.