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Erschienen in: Endocrine 1/2020

14.01.2020 | Original Article

Inhibition of thioredoxin 2 by intracellular methylglyoxal accumulation leads to mitochondrial dysfunction and apoptosis in INS-1 cells

verfasst von: Chongxiao Liu, Baige Cao, Qianren Zhang, Yifan Zhang, Xueru Chen, Xiang Kong, Yan Dong

Erschienen in: Endocrine | Ausgabe 1/2020

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Abstract

Purpose

To investigate the role of thioredoxin 2 (Trx2) inhibition induced by intracellular methylglyoxal (MGO) in pancreatic beta-cell mitochondrial dysfunction and apoptosis.

Methods

Rat pancreatic beta-cell line INS-1 cells were treated with Glo1 siRNAs or exogenous MGO to increase intracellular MGO. AGEs formation was detected by ELISA and mitochondrial ROS was detected by probe MitoSOX. Transmission electron microscopy (TEM) analysis and ATP content were measured to evaluate mitochondrial function. Trx2 expression was manipulated by overexpression with recombinant Trx2 lentivirus or knockdown with Trx2 siRNAs, and effects on apoptosis and insulin secretion were measured by flow cytometry and ELISA, respectively.

Results

The increase of intracellular MGO by Glo1 blockage or MGO treatment led to advanced glycation end products (AGEs) overproduction, mitochondrial ROS increase, and insulin secretion paralysis. These were probably due to MGO-induced inhibition of mitochondrial Trx2. Trx2 inhibition by blockage of either Glo1 or Trx2 impaired mitochondrial integrity, inhibited cytochrome C oxidases subunit 1 and 4 (Cox1 and Cox4) expression and further reduced ATP generation, and all of these might lead to insulin paralysis; whereas Trx2 overexpression partially reversed MGO-induced oxidative stress, attenuated insulin secretion by preventing mitochondrial damage. Trx2 overexpression also retarded MGO-induced apoptosis of INS-1 cell through inhibiting ASK1 activation and downregulation of the ASK1-p38 MAPK pathway.

Conclusions

Our results reveal a possible mechanism for beta-cell oxidative damage upon intracellular MGO-induced Trx2 inactivation and mitochondrial dysfunction and apoptosis.
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Metadaten
Titel
Inhibition of thioredoxin 2 by intracellular methylglyoxal accumulation leads to mitochondrial dysfunction and apoptosis in INS-1 cells
verfasst von
Chongxiao Liu
Baige Cao
Qianren Zhang
Yifan Zhang
Xueru Chen
Xiang Kong
Yan Dong
Publikationsdatum
14.01.2020
Verlag
Springer US
Erschienen in
Endocrine / Ausgabe 1/2020
Print ISSN: 1355-008X
Elektronische ISSN: 1559-0100
DOI
https://doi.org/10.1007/s12020-020-02191-x

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