Inhibition of mitochondrial phosphate carrier prevents high phosphate-induced superoxide generation and vascular calcification.

Nhung Thi Nguyen, Tuyet Thi Nguyen, Ha Thu Nguyen, Ji-Min Lee, Min-Ji Kim, Xu-Feng Qi, Seung-Kuy Cha, In-Kyu Lee, Kyu-Sang Park

Experimental & molecular medicine 2023 Mar

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Vascular calcification is a serious complication of hyperphosphatemia that causes cardiovascular morbidity and mortality. Previous studies have reported that plasmalemmal phosphate (Pi) transporters, such as PiT-1/2, mediate depolarization, Ca2+ influx, oxidative stress, and calcific changes in vascular smooth muscle cells (VSMCs). However, the pathogenic mechanism of mitochondrial Pi uptake in vascular calcification associated with hyperphosphatemia has not been elucidated. We demonstrated that the phosphate carrier (PiC) is the dominant mitochondrial Pi transporter responsible for high Pi-induced superoxide generation, osteogenic gene upregulation, and calcific changes in primary VSMCs isolated from rat aortas. Notably, acute incubation with high Pi markedly increased the protein abundance of PiC via ERK1/2- and mTOR-dependent translational upregulation. Genetic suppression of PiC prevented Pi-induced ERK1/2 activation, superoxide production, osteogenic differentiation, and vascular calcification of VSMCs in vitro and aortic rings ex vivo. Pharmacological inhibition of mitochondrial Pi transport using butyl malonate (BMA) or mersalyl abolished all pathologic changes involved in high Pi-induced vascular calcification. BMA or mersalyl also effectively prevented osteogenic gene upregulation and calcification of aortas from 5/6 subtotal nephrectomized mice fed a high-Pi diet. Our results suggest that mitochondrial Pi uptake via PiC is a critical molecular mechanism mediating mitochondrial superoxide generation and pathogenic calcific changes, which could be a novel therapeutic target for treating vascular calcification associated with hyperphosphatemia. © 2023. The Author(s).

Citation

Nhung Thi Nguyen, Tuyet Thi Nguyen, Ha Thu Nguyen, Ji-Min Lee, Min-Ji Kim, Xu-Feng Qi, Seung-Kuy Cha, In-Kyu Lee, Kyu-Sang Park. Inhibition of mitochondrial phosphate carrier prevents high phosphate-induced superoxide generation and vascular calcification. Experimental & molecular medicine. 2023 Mar;55(3):532-540