title: Intracellular alkalinization by phosphate uptake via type III sodium-phosphate cotransporter participates in high-phosphate-induced mitochondrial oxidative stress and defective insulin secretion.
abstract: Elevated plasma levels of inorganic phosphate (Pi) are harmful, causing, among other complications, vascular calcification and defective insulin secretion. The underlying molecular mechanisms of these complications remain poorly understood. We demonstrated the role of Pitransport across the plasmalemma on Pitoxicity in INS-1E rat clonal β cells and rat pancreatic islet cells. Type III sodium-phosphate cotransporters (NaPis) are the predominant Pitransporters expressed in insulin-secreting cells. Transcript and protein levels of sodium-dependent phosphate transporter 1 and 2 (PiT-1 and -2), isotypes of type III NaPi, were up-regulated by high-Piincubation. In patch-clamp experiments, extracellular Pielicited a Na+-dependent, inwardly rectifying current, which was markedly reduced under acidic extracellular conditions. Cellular uptake of Pielicited cytosolic alkalinization; intriguingly, this pH change facilitated Pitransport into the mitochondrial matrix. Increased mitochondrial Piuptake accelerated superoxide generation, mitochondrial permeability transition (mPT), and endoplasmic reticulum stress-mediated translational attenuation, leading to reduced insulin content and impaired glucose-stimulated insulin secretion. Silencing of PiT-1/2 prevented Pi-induced superoxide generation and mPT, and restored insulin secretion. We propose that Pitransport across the plasma membrane and consequent cytosolic alkalinization could be a therapeutic target for protection from Pitoxicity in insulin-secreting cells, as well as in other cell types.-Nguyen, T. T., Quan, X., Xu, S., Das, R., Cha, S.-K., Kong, I. D., Shong, M., Wollheim, C. B., Park, K.-S. Intracellular alkalinization by phosphate uptake via type III sodium-phosphate cotransporter participates in high-phosphate-induced mitochondrial oxidative stress and defective insulin secretion.
authors: Department of Physiology, Wonju College of Medicine, Yonsei University, Wonju, Korea.|Department of Physiology, Tan-Tao University College of Medicine, Long An, Vietnam.
authors: Tuyet Thi
authors: TT
authors: Nguyen
authors: Department of Physiology, Wonju College of Medicine, Yonsei University, Wonju, Korea.
authors: Xianglan
authors: X
authors: Quan
authors: Department of Physiology, Wonju College of Medicine, Yonsei University, Wonju, Korea.
authors: Shanhua
authors: S
authors: Xu
authors: Department of Physiology, Wonju College of Medicine, Yonsei University, Wonju, Korea.
authors: Ranjan
authors: R
authors: Das
authors: Department of Physiology, Wonju College of Medicine, Yonsei University, Wonju, Korea.|Mitohormesis Translational Research Center, Wonju College of Medicine, Yonsei University, Wonju, Korea.
authors: Seung-Kuy
authors: SK
authors: Cha
authors: Department of Physiology, Wonju College of Medicine, Yonsei University, Wonju, Korea.
authors: In Deok
authors: ID
authors: Kong
authors: Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon, Korea; and.
authors: Minho
authors: M
authors: Shong
authors: Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
authors: Claes B
authors: CB
authors: Wollheim
authors: Department of Physiology, Wonju College of Medicine, Yonsei University, Wonju, Korea; qsang@yonsei.ac.kr.|Mitohormesis Translational Research Center, Wonju College of Medicine, Yonsei University, Wonju, Korea.
authors: Kyu-Sang
authors: KS
authors: Park
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D006706:Homeostasis / Q000187:drug effects; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D017136:Ion Transport / Q000235:genetics*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010710:Phosphates / Q000494:pharmacology*; D051381:Rats; D050611:Sodium-Phosphate Cotransporter Proteins, Type III / Q000378:metabolism*
chemical_list: D007328:Insulin; D010710:Phosphates; D050611:Sodium-Phosphate Cotransporter Proteins, Type III
keywords: endoplasmic reticulum stress; inorganic phosphate; mitochondrial permeability transition; pancreatic β cells; superoxide