title: Mitochondrial oxidative stress mediates high-phosphate-induced secretory defects and apoptosis in insulin-secreting cells.
abstract: Inorganic phosphate (Pi) plays an important role in cell signaling and energy metabolism. In insulin-releasing cells, Pi transport into mitochondria is essential for the generation of ATP, a signaling factor in metabolism-secretion coupling. Elevated Pi concentrations, however, can have toxic effects in various cell types. The underlying molecular mechanisms are poorly understood. Here, we have investigated the effect of Pi on secretory function and apoptosis in INS-1E clonal β-cells and rat pancreatic islets. Elevated extracellular Pi (1~5 mM) increased the mitochondrial membrane potential (ΔΨm), superoxide generation, caspase activation, and cell death. Depolarization of the ΔΨm abolished Pi-induced superoxide generation. Butylmalonate, a nonselective blocker of mitochondrial phosphate transporters, prevented ΔΨm hyperpolarization, superoxide generation, and cytotoxicity caused by Pi. High Pi also promoted the opening of the mitochondrial permeability transition (PT) pore, leading to apoptosis, which was also prevented by butylmalonate. The mitochondrial antioxidants mitoTEMPO or MnTBAP prevented Pi-triggered PT pore opening and cytotoxicity. Elevated extracellular Pi diminished ATP synthesis, cytosolic Ca(2+) oscillations, and insulin content and secretion in INS-1E cells as well as in dispersed islet cells. These parameters were restored following preincubation with mitochondrial antioxidants. This treatment also prevented high-Pi-induced phosphorylation of ER stress proteins. We propose that elevated extracellular Pi causes mitochondrial oxidative stress linked to mitochondrial hyperpolarization. Such stress results in reduced insulin content and defective insulin secretion and cytotoxicity. Our data explain the decreased insulin content and secretion observed under hyperphosphatemic states.
authors: Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea;
authors: Tuyet Thi
authors: TT
authors: Nguyen
authors: Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea;
authors: Xianglan
authors: X
authors: Quan
authors: Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea;
authors: Kyu-Hee
authors: KH
authors: Hwang
authors: Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea;
authors: Shanhua
authors: S
authors: Xu
authors: Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea;
authors: Ranjan
authors: R
authors: Das
authors: Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea;
authors: Seong-Kyung
authors: SK
authors: Choi
authors: Nestlé Institute of Health Sciences, Lausanne, Switzerland, and.
authors: Andreas
authors: A
authors: Wiederkehr
authors: Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
authors: Claes B
authors: CB
authors: Wollheim
authors: Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea;
authors: Seung-Kuy
authors: SK
authors: Cha
authors: Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea; qsang@yonsei.ac.kr.
authors: Kyu-Sang
authors: KS
authors: Park
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D018384:Oxidative Stress / Q000502:physiology*; D010710:Phosphates / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism
chemical_list: D007328:Insulin; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010710:Phosphates; D017382:Reactive Oxygen Species; D013481:Superoxides
keywords: ER stress; hyperphosphatemia; insulin secretion; mitochondrial permeability transition pore; superoxide