Role of inorganic polyphosphate in cellular pharmacological models of Parkinson's disease

Parkinson’s Disease (PD) is a complex neurodegenerative disorder. While the mechanisms increasing neuronal death remain still mostly unknown, mitochondrial dysfunction has been broadly described as a crucial component of the etiopathology of PD. Specifically, increased oxidative stress and mitochondrial fission, along with dysfunctional mitochondrial specific autophagy (mitophagy), and decreased energy production from oxidative phosphorylation (OXPHOS) are all well-known contributors to the mitochondrial dysfunction observed in PD. However, the mechanisms that link these processes remain mostly unknown. Inorganic polyphosphate (polyP) is a ubiquitous polymer that exhibits a high mitochondrial co-localization in mammals. The key role played by polyP in the cellular response to diverse types of stressors has already been proposed and demonstrated in multiple organisms. The central goal of this study was to determine the role of mitochondrial polyP in cellular, pharmacologically-induced models of PD. To accomplish this, we created SH-SY5Y and HEK293 cells enzymatically depleted of mitochondrial polyP by stable transfection with yeast exopolyphosphatase (scPPX). We then treated both Wt and mitochondrial polyP(-) (MitoPPX) cells with 6-hydroxydopmaine (6-OHDA), which is a well-known neurotoxin, commonly used in cellular and animal models of PD. Importantly, 6-OHDA does not induce the formation of Lewy bodies. In fact, its main mechanism of action is to undergo oxidation and generate massive amounts of ROS. This is important for our project, as it allowed us to dissect the role of polyP as a bioenergetics regulator from its role as a chaperone, which has been demonstrated in different systems and models. Our experiments showed that, both basally and upon treatment with 6-OHDA, MitoPPX cells exhibit decreased levels of ATP and increased levels of ROS, when compared to Wt. This, led to increased mitochondrial fission and fragmentation, as well as to increased mitophagy. Based on these results we propose that mitochondrial polyP could be crucial in cellular protection against 6-OHDA, through its crucial role in bioenergetics and, therefore, the regulation of intracellular levels of ROS.M.S.Includes bibliographical reference