Depletion of mitochondrial polyP levels increase the phosphorylation of AMPK protein and compromises oxygen consumption in SH-SY5Y cells.

Abstract

Inorganic polyphosphate (polyP) is a highly negatively charged polymer that is well-conserved through evolution and present in every studied organism. PolyP is composed of orthophosphates linked by high-energy phosphoanhydride bonds. While its metabolism has been characterized in microorganisms, it is poorly explored in mammals. Previous studies showed that polyP can be found in diverse mammalian subcellular compartments but that it is especially abundant in mitochondria, where it could function as a key regulator of mitochondrial bioenergetics, via an unknown mechanism. We have demonstrated that decreased levels of polyP in mammalian mitochondria induce the dysfunction of the organelle, which results in compromised bioenergetics. AMP-activated protein kinase (AMPK) is a key energy gauge, and it regulates diverse metabolic processes. Therefore, this study aimed to investigate whether polyP levels can participate in the activation of AMPK and how this pathway can impact mitochondrial physiology and represent an important and novel approach that can contribute to improving our knowledge of mammalian bioenergetics and mitochondrial physiology. We used undifferentiated and differentiated SH-SY5Y cells, under wild-type conditions and after the enzymatical depletion of mitochondrial polyP (MitoPPX). Our data show that depletion of mitochondrial polyP impacts mitochondrial bioenergetics by affecting ATP-linked respiration. It also increases the levels of activated AMPK in differentiated SH-SY5Y cells. Our findings suggest an important novel role of polyP as a key regulator of cellular bioenergetics probably via the regulation of the AMPK pathway. AMPK activity and mitochondrial dysfunction are commonly implicated in the pathogenesis of many neurodegenerative diseases. Therefore, the manipulation of the metabolism of polyP in neuronal cells might represent a plausible target for developing therapeutic approaches against neurodegenerative diseases.