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Intracellular alkalinization by phosphate uptake via type III sodium–phosphate cotransporter participates in high‐phosphate‐induced mitochondrial oxidative stress and defective insulin secretion
Author(s) -
Nguyen Tuyet Thi,
Quan Xianglan,
Xu Shanhua,
Das Ranjan,
Cha SeungKuy,
Kong Deok,
Shong Minho,
Wollheim Claes B.,
Park KyuSang
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201600455rr
Subject(s) - cotransporter , intracellular , extracellular , insulin , chemistry , oxidative stress , mitochondrial permeability transition pore , secretion , intracellular ph , mitochondrion , biochemistry , sodium , endocrinology , medicine , biology , programmed cell death , apoptosis , organic chemistry
Elevated plasma levels of inorganic phosphate (Pi) are harmful, causing, among other complications, vascular calcification anddefective insulin secretion. Theunderlyingmolecular mechanisms of these complications remain poorly understood. We demonstrated the role of P i transport across the plasmalemma on P i toxicity in INS‐1E rat clonal b cells and rat pancreatic islet cells. Type III sodium–phosphate cotransporters (NaPis) are the predominant P i transporters expressed in insulin‐secreting cells. Transcript and protein levels of sodium‐dependent phosphate transporter 1 and 2 (PiT‐1 and‐2), isotypesof typeIIINaPi, were up‐regulatedbyhigh‐P i incubation. Inpatch‐clampexperiments, extracellular P i elicited a Na + ‐dependent, inwardly rectifying current, which was markedly reduced under acidic extracellular conditions. Cellular uptake of P i elicited cytosolic alkalinization; intriguingly, this pH change facilitated P i transport into the mitochondrialmatrix. Increased mitochondrial P i uptake accelerated superoxide generation, mitochondrial permeability transition (mPT), andendoplasmic reticulumstress‐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. Wepropose that P i transport across the plasma membrane and consequent cytosolic alkalinization could be a therapeutic target for protection from P i toxicity in insulin‐secreting cells, aswell 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. FASEB J. 30, 3979–3988 (2016). www.fasebj.org