# Inorganic Polyphosphate in Mammals: Mechanisms, Maladies, and Moving Forward

## TL;DR

This review explores the roles and mechanisms of inorganic polyphosphate in mammals, highlighting its functions in cellular processes and diseases, while identifying gaps in understanding and research priorities.

## Contribution

The paper integrates molecular mechanisms with disease physiology and outlines key gaps and priorities for advancing polyphosphate research in mammals.

## Key findings

- Polyphosphate modulates mitochondrial permeability transition pore and activates factor XII in coagulation.
- Potential links between polyphosphate and neurodegeneration, cancer, and tissue regeneration are suggested.
- Technical limitations hinder detection and quantification of polyphosphate, complicating interpretation of its biological effects.

## Abstract

Inorganic polyphosphate is highly conserved, critical, yet poorly understood polymer that regulates diverse cellular functions in mammals. Its importance is well established in coagulation, inflammation, mitochondrial function, and stress responses, though the molecular mechanisms for these effects remain only partly understood. Fundamental questions also persist regarding its physiological concentration, chain-length distributions, and the mechanisms that regulate its behavior in specific cellular compartments. Progress is limited by the absence of a known mammalian polyphosphate-synthesizing enzyme. Despite this, recent studies have broadened the scope of polyphosphate biology, suggesting roles in protein phase separation, ATP-independent chaperone activity, metabolic regulation, and intracellular signaling. Polyphosphate modulates the mitochondrial permeability transition pore through calcium-dependent regulation and activates factor XII in coagulation. Findings have also introduced potential connections between polyphosphate and processes such as neurodegeneration, cancer, and tissue regeneration. Despite this expanding landscape, many biological effects remain difficult to interpret due to incomplete mapping of protein targets and longstanding technical limitations in detecting and quantifying polyP. This review integrates molecular protein-interaction mechanisms with compartment-specific functions and disease physiology, providing a clearer mechanistic framework while identifying key conceptual and methodological gaps and outlining priorities for advancing polyphosphate research in mammalian systems.