Cellular calcification induced by inorganic polyphosphate involves ATP depletion and opening of the mitochondrial permeability transition pore (mPTP)

Abstract

Inorganic polyphosphate (polyP) is a linear polymer containing tens to hundreds of orthophosphate residues linked by high‐energy phosphoanhydride bonds. PolyP promotes osteocalcification and bone mineralization in both mouse and human osteoblastic cells. In the present study, we examined the molecular mechanism by which polyP affects mitochondrial metabolism to promote cellular calcification in MC 3T3‐E1 osteoblastic cells. The cellular content of adenosine triphosphate ( ATP ) was diminished one day after polyP treatment, and this was accompanied by increased conversion to adenosine diphosphate. Furthermore, mitochondrial membrane potential was significantly decreased in polyP‐treated cells. These results suggest that the depletion of intracellular ATP and the decrease in mitochondrial membrane potential induced by polyP treatment may be a trigger to promote cell calcification.

The dynamic relationship between inorganic polyphosphate and adenosine triphosphate in human non‐small cell lung cancer H1299 cells

“…This phenomenon was consistent with the T98G cell line used in this study (Fig. 1B ), and it also aligned with the findings of our previous study involving the same cell line [ 29 ]. In fibroblast‐derived cell lines, polyP promotes cell proliferation by modulating the activity of basic fibroblast growth factor (FGF‐2) [ 25 ].…”

“…The variations in ATP levels among different cell types can be attributed to the varying amounts of endogenous ATP present in each cell type. ATP depletion in polyP-treated cells has also been reported in a previous study involving the mouse osteoblastic cell line MC3T3-E1 [29]. Our findings indicate that while pyruvate serves as a substrate in cellular energy metabolism and can contribute to ATP production, there are situations where pyruvate may not effectively restore ATP levels in cancer cells.…”

“…The density of mitochondria increases when mitochondrial polyP is depleted by expressing the yeast‐derived exopolyphosphatase in mitochondria [28]. Our previous reports also suggested that polyP‐treated mouse osteoblastic cells exhibit low mitochondrial density in electron microscopy [29,30]. They collectively suggest that polyP plays a significant role both as an extracellular drug and in endogenous physiological processes.…”

Inorganic Polyphosphates As Storage for and Generator of Metabolic Energy in the Extracellular Matrix

“…171 Recently, it has been reported that a decrease of mitochondrial membrane potential by opening mPTP pores is associated with a rise in calcification of polyP-treated MC3T3-E1 osteoblastic cells. 172…”

“…Interestingly, polyP has also been found to be an modulator (activator) of mTORC1 (target of rapamycin complex 1), a complex that acts as an intracellular homeostatic ATP sensor by activating a series of anabolic metabolic pathways . Recently, it has been reported that a decrease of mitochondrial membrane potential by opening mPTP pores is associated with a rise in calcification of polyP-treated MC3T3-E1 osteoblastic cells …”