Inorganic Polyphosphate (Polyp) Promotes Protein Aggregation To Protect Mitochondria Against Stress

Inorganic polyphosphate (polyP) is a ubiquitous biological polymer, well-conserved throughout the evolution and various species. Isoenergetic with ATP, polyP is composed of multiple subunits of orthophosphate, linked together by phosphoanhydride bonds. We previously showed that this polymer highly localizes in mammalian mitochondria, where it plays different roles. In fact, cells with reduced amounts of mitochondrial polyP showed higher levels of cell death in response to calcium dyshomeostasis. Here we show that the chaperone effect of polyP is mainly mitochondrial. Moreover, we also show that decreased amount of polyP also decreases cells resistance to heat-shock induced cytotoxicity. In the absence of polyP, cell death is also increased after the addition of aggregated α- synuclein. Interestingly, in brains from mice showing amyloid plaques, polyP levels were increased. Our data also shows that the chaperoning activity of polyP is independent on any transcriptional changes. These findings are in agreement with the recently proposed role of polyP as a molecular chaperone, involved in cell stress response. We hypothesize that polyP is crucial for the mitochondrial formation of fibrils, preventing protein misfolding toxicity.