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.