Mitochondrial oxidative stress mediates high-phosphate-induced secretory defects and apoptosis in insulin-secreting cells

Tuyet Thi Nguyen, Xianglan Quan, Kyu Hee Hwang, Shanhua Xu, Ranjan Das, Seong Kyung Choi, Andreas Wiederkehr, Claes B. Wollheim, Seungkuy Cha, Kyusang Park

Research output: Contribution to journalArticle

15 Citations (Scopus)

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 (Δ ψm), superoxide generation, caspase activation, and cell death. Depolarization of the Δ ψm abolished Pi-induced superoxide generation. Butylmalonate, a nonselective blocker of mitochondrial phosphate transporters, prevented Δ ψm 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 Ca2+ 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.

Original languageEnglish
Pages (from-to)E933-E941
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume308
Issue number11
DOIs
Publication statusPublished - 2015 Jan 1

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Insulin-Secreting Cells
Oxidative Stress
Phosphates
Insulin
Apoptosis
Superoxides
Islets of Langerhans
Antioxidants
Adenosine Triphosphate
Phosphate Transport Proteins
Mitochondrial Membrane Potential
Poisons
Caspases
Heat-Shock Proteins
Energy Metabolism
Permeability
Mitochondria
Cell Death
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

Cite this

Nguyen, Tuyet Thi ; Quan, Xianglan ; Hwang, Kyu Hee ; Xu, Shanhua ; Das, Ranjan ; Choi, Seong Kyung ; Wiederkehr, Andreas ; Wollheim, Claes B. ; Cha, Seungkuy ; Park, Kyusang. / Mitochondrial oxidative stress mediates high-phosphate-induced secretory defects and apoptosis in insulin-secreting cells. In: American Journal of Physiology - Endocrinology and Metabolism. 2015 ; Vol. 308, No. 11. pp. E933-E941.
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Mitochondrial oxidative stress mediates high-phosphate-induced secretory defects and apoptosis in insulin-secreting cells. / Nguyen, Tuyet Thi; Quan, Xianglan; Hwang, Kyu Hee; Xu, Shanhua; Das, Ranjan; Choi, Seong Kyung; Wiederkehr, Andreas; Wollheim, Claes B.; Cha, Seungkuy; Park, Kyusang.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 308, No. 11, 01.01.2015, p. E933-E941.

Research output: Contribution to journalArticle

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T1 - Mitochondrial oxidative stress mediates high-phosphate-induced secretory defects and apoptosis in insulin-secreting cells

AU - Nguyen, Tuyet Thi

AU - Quan, Xianglan

AU - Hwang, Kyu Hee

AU - Xu, Shanhua

AU - Das, Ranjan

AU - Choi, Seong Kyung

AU - Wiederkehr, Andreas

AU - Wollheim, Claes B.

AU - Cha, Seungkuy

AU - Park, Kyusang

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N2 - 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 (Δ ψm), superoxide generation, caspase activation, and cell death. Depolarization of the Δ ψm abolished Pi-induced superoxide generation. Butylmalonate, a nonselective blocker of mitochondrial phosphate transporters, prevented Δ ψm 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 Ca2+ 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.

AB - 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 (Δ ψm), superoxide generation, caspase activation, and cell death. Depolarization of the Δ ψm abolished Pi-induced superoxide generation. Butylmalonate, a nonselective blocker of mitochondrial phosphate transporters, prevented Δ ψm 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 Ca2+ 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.

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