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Review
. 2021 Jan:163:105211.
doi: 10.1016/j.phrs.2020.105211. Epub 2020 Oct 1.

Is there a link between inorganic polyphosphate (polyP), mitochondria, and neurodegeneration?

Emily A Borden  1 , Matthew Furey  1 , Nicholas J Gattone  1 , Vedangi D Hambardikar  2 , Xiao Hua Liang  1 , Ernest R Scoma  1 , Antonella Abou Samra  1 , LaKeshia R D-Gary  1 , Dayshaun J Dennis  1 , Daniel Fricker  1 , Cindy Garcia  1 , ZeCheng Jiang  1 , Shariq A Khan  1 , Dheenadhayalan Kumarasamy  1 , Hasmitha Kuppala  1 , Savannah Ringrose  1 , Evan J Rosenheim  1 , Kimberly Van Exel  2 , Hemanth Sai Vudhayagiri  1 , Jiarui Zhang  2 , Zhaowen Zhang  1 , Mariona Guitart-Mampel  1 , Pedro Urquiza  1 , Maria E Solesio  3
Affiliations
Review

Is there a link between inorganic polyphosphate (polyP), mitochondria, and neurodegeneration?

Emily A Borden et al. Pharmacol Res. 2021 Jan.

Abstract

Mitochondrial dysfunction - including increased apoptosis, calcium and protein dyshomeostasis within the organelle, and dysfunctional bioenergetics and oxidative status - is a common, early feature in all the major neurodegenerative diseases, including Alzheimer's Disease (AD) and Parkinson's Disease (PD). However, the exact molecular mechanisms that drive the organelle to dysfunction and ultimately to failure in these conditions are still not well described. Different authors have shown that inorganic polyphosphate (polyP), an ancient and well-conserved molecule, plays a key role in the regulation of mitochondrial physiology under basal conditions. PolyP, which is present in all studied organisms, is composed of chains of orthophosphates linked together by highly energetic phosphoanhydride bonds, similar to those found in ATP. This polymer shows a ubiquitous distribution, even if a high co-localization with mitochondria has been reported. It has been proposed that polyP might be an alternative to ATP for cellular energy storage in different organisms, as well as the implication of polyP in the regulation of many of the mitochondrial processes affected in AD and PD, including protein and calcium homeostasis. Here, we conduct a comprehensive review and discussion of the bibliography available regarding the role of polyP in the mitochondrial dysfunction present in AD and PD. Taking into account the data presented in this review, we postulate that polyP could be a valid, innovative and, plausible pharmacological target against mitochondrial dysfunction in AD and PD. However, further research should be conducted to better understand the exact role of polyP in neurodegeneration, as well as the metabolism of the polymer, and the effect of different lengths of polyP on cellular and mitochondrial physiology.

Keywords: Alzheimer’s disease; Inorganic polyphosphate; Mitochondria; Neurodegeneration; Parkinson’s disease; polyP.

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Conflict of interest statement

CONFLICT OF INTEREST

The authors declare no conflict of interest

Figures

Figure 1.
Figure 1.. Role of polyP in different cellular processes in which mitochondrial physiology is affected and are dysfunctional in AD an PD.
Various authors have shown the important role played by polyP in cell signaling (acting as a gliotransmitter and regulating mitochondrial calcium buffering and thus calcium signaling; energy metabolism) as an alternative energy storage form; inflammation (mainly located in the extracellular space and connecting inflammation and coagulation; and in the chaperoning and amyloid aggregation regulation) contributes to proteostasis within the organelle and the cell. Moreover, polyP has also been proposed to play a role in the direct regulation of apoptosis, which is the main cause of cell death within the central nervous system in all neurodegenerative diseases. All these processes share some common features: they are affected in AD and PD, mitochondria play a crucial role in them, and they are tightly inter-connected and inter-regulated. While many authors have demonstrated the effect of polyP on these processes, some of the data regarding the protective or deleterious action of the polymer seem to be contradictory. The size and the exact intra-cellular location of polyP could explain these differences. However, more research should be conducted to determine the exact metabolism of the polymer, as well as the optimal conditions in which polyP protects cellular populations against the mitochondrial dysfunction and the subsequent increased apoptotic cell death that is observed in AD and PD.
Figure 2.
Figure 2.. Role of polyP in protein biology.
Various authors, using in vitro and in vivo models, have shown the protective effect of polyP against increased proteotoxicity in both A. amyloidogenic and, B. non-amyloidogenic proteins. While in the first case, polyP promotes the quick formation of insoluble fibrils, avoiding the presence of the toxic, soluble, oligomeric intermediates, in the non-amyloidogenic proteins, polyP promotes their refolding, into their functional conformation. Thereafter, polyP can be recycled, conserving its chaperoning activity. The most common insults known to increase protein dyshomeostasis are heat shock, variations in the cellular and/or mitochondrial pH, and increased presence of ROS. In the case of AD and PD, increased ROS – which is tightly related to mitochondrial dysfunction – have been broadly reported in different cellular and animal models of the disease.
Figure 3:
Figure 3:. Role of polyP in mitochondrial calcium buffering.
Mitochondria is a key organelle in the calcium buffering system, which is closely related to the signaling mediated by the cation. Interestingly, both calcium buffering and signaling are affected and dysfunctional in various neurodegenerative disorders, including AD and PD. A. While polyP and calcium are capable of forming reversible bonds, which can dissociate and contribute to buffering the levels of the cation, under the proper physiological conditions, B. the bound of orthophosphate and calcium is irreversible and it forms a crystal, which precipitates. Dysregulated calcium homeostasis within mitochondria will induce the opening of the mPTP and the consequent apoptotic cell death. Please, note that blue dots simbolize calcium anions, while red dots represent polyP.
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