The role of PGC-1α and MRP1 in lead-induced mitochondrial toxicity in testicular Sertoli cells

Zhen Li; Xi Liu; Lu Wang; Yan Wang; Chuang Du; Siyuan Xu; Yucheng Zhang; Chunhong Wang; Chengfeng Yang

doi:10.1016/j.tox.2016.05.016

The role of PGC-1α and MRP1 in lead-induced mitochondrial toxicity in testicular Sertoli cells

Zhen Li, Xi Liu, Lu Wang, Yan Wang, Chuang Du, Siyuan Xu, Yucheng Zhang, Chunhong Wang, Chengfeng Yang

Markey Cancer Center / Cancer Research Priority Initiative

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

Abstract

The lead-induced toxic effect on mitochondria in Sertoli cells is not well studied and the underlying mechanism is poorly understood. Here we reported the potential role of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and multidrug resistance protein 1 (MRP1) in lead acetate-induced mitochondrial toxicity in mouse testicular Sertoli cells TM4 line. We found that lead acetate treatment significantly reduced the expression level of PGC-1α, but increased the level of MRP1 in mitochondria of TM4 cells. To determine the role of PGC-1α and MRP1 in lead acetate-induced mitochondrial toxicity, we then generated PGC-1α stable overexpression and MRP1 stable knockdown TM4 cells, respectively. The lead acetate treatment caused TM4 cell mitochondrial ultrastructure damages, a decrease in ATP synthesis, an increase in ROS levels, and apoptotic cell death. In contrast, stably overexpressing PGC-1α significantly ameliorated the lead acetate treatment-caused mitochondrial toxicity and apoptosis. Moreover, it was also found that stably knocking down the level of MRP1 increased the TM4 cell mitochondrial lead-accumulation by 4-6 folds. Together, the findings from this study suggest that PGC-1α and MRP1 plays important roles in protecting TM4 cells against lead-induced mitochondrial toxicity, providing a better understanding of lead-induced mitochondrial toxicity.

Original language	English
Pages (from-to)	39-48
Number of pages	10
Journal	Toxicology
Volume	355-356
DOIs	https://doi.org/10.1016/j.tox.2016.05.016
State	Published - Apr 29 2016

Bibliographical note

Publisher Copyright:
© 2016 Elsevier Ireland Ltd.

Funding

The authors thank all members in Professor CH. Wang’s laboratory in Wuhan University for their valuable assistances and Dr. Weihuang Liu from the School of Basic Medical Sciences of Wuhan University for her technical assistance with the flow cytometry. This work was supported by the National Natural Science Foundation of China (grant number 81172628 ) and the Fundamental Research Funds for the Central Universities (grant number 2014305020201 ) and the Open Fund of Hubei Provincial Key Laboratory for Applied Toxicology , Hubei Provincial Academy for Preventive Medicine (grant number 20140002 ).

Funders	Funder number
Hubei Provincial Academy for Preventive Medicine	20140002
Hubei Provincial Key Laboratory for Applied Toxicology
National Natural Science Foundation of China (NSFC)	81172628
Fundamental Research Funds for the Central Universities	2014305020201

Keywords

Lead acetate
MRP1
Mitochondrial toxicity
PGC-1α
Sertoli cell

ASJC Scopus subject areas

Toxicology

Access to Document

10.1016/j.tox.2016.05.016

Cite this

@article{08a82e5b689346758e81892c1fe4cebd,

title = "The role of PGC-1α and MRP1 in lead-induced mitochondrial toxicity in testicular Sertoli cells",

abstract = "The lead-induced toxic effect on mitochondria in Sertoli cells is not well studied and the underlying mechanism is poorly understood. Here we reported the potential role of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and multidrug resistance protein 1 (MRP1) in lead acetate-induced mitochondrial toxicity in mouse testicular Sertoli cells TM4 line. We found that lead acetate treatment significantly reduced the expression level of PGC-1α, but increased the level of MRP1 in mitochondria of TM4 cells. To determine the role of PGC-1α and MRP1 in lead acetate-induced mitochondrial toxicity, we then generated PGC-1α stable overexpression and MRP1 stable knockdown TM4 cells, respectively. The lead acetate treatment caused TM4 cell mitochondrial ultrastructure damages, a decrease in ATP synthesis, an increase in ROS levels, and apoptotic cell death. In contrast, stably overexpressing PGC-1α significantly ameliorated the lead acetate treatment-caused mitochondrial toxicity and apoptosis. Moreover, it was also found that stably knocking down the level of MRP1 increased the TM4 cell mitochondrial lead-accumulation by 4-6 folds. Together, the findings from this study suggest that PGC-1α and MRP1 plays important roles in protecting TM4 cells against lead-induced mitochondrial toxicity, providing a better understanding of lead-induced mitochondrial toxicity.",

keywords = "Lead acetate, MRP1, Mitochondrial toxicity, PGC-1α, Sertoli cell",

author = "Zhen Li and Xi Liu and Lu Wang and Yan Wang and Chuang Du and Siyuan Xu and Yucheng Zhang and Chunhong Wang and Chengfeng Yang",

note = "Publisher Copyright: {\textcopyright} 2016 Elsevier Ireland Ltd.",

year = "2016",

month = apr,

day = "29",

doi = "10.1016/j.tox.2016.05.016",

language = "English",

volume = "355-356",

pages = "39--48",

}

TY - JOUR

T1 - The role of PGC-1α and MRP1 in lead-induced mitochondrial toxicity in testicular Sertoli cells

AU - Li, Zhen

AU - Liu, Xi

AU - Wang, Lu

AU - Wang, Yan

AU - Du, Chuang

AU - Xu, Siyuan

AU - Zhang, Yucheng

AU - Wang, Chunhong

AU - Yang, Chengfeng

PY - 2016/4/29

Y1 - 2016/4/29

N2 - The lead-induced toxic effect on mitochondria in Sertoli cells is not well studied and the underlying mechanism is poorly understood. Here we reported the potential role of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and multidrug resistance protein 1 (MRP1) in lead acetate-induced mitochondrial toxicity in mouse testicular Sertoli cells TM4 line. We found that lead acetate treatment significantly reduced the expression level of PGC-1α, but increased the level of MRP1 in mitochondria of TM4 cells. To determine the role of PGC-1α and MRP1 in lead acetate-induced mitochondrial toxicity, we then generated PGC-1α stable overexpression and MRP1 stable knockdown TM4 cells, respectively. The lead acetate treatment caused TM4 cell mitochondrial ultrastructure damages, a decrease in ATP synthesis, an increase in ROS levels, and apoptotic cell death. In contrast, stably overexpressing PGC-1α significantly ameliorated the lead acetate treatment-caused mitochondrial toxicity and apoptosis. Moreover, it was also found that stably knocking down the level of MRP1 increased the TM4 cell mitochondrial lead-accumulation by 4-6 folds. Together, the findings from this study suggest that PGC-1α and MRP1 plays important roles in protecting TM4 cells against lead-induced mitochondrial toxicity, providing a better understanding of lead-induced mitochondrial toxicity.

AB - The lead-induced toxic effect on mitochondria in Sertoli cells is not well studied and the underlying mechanism is poorly understood. Here we reported the potential role of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and multidrug resistance protein 1 (MRP1) in lead acetate-induced mitochondrial toxicity in mouse testicular Sertoli cells TM4 line. We found that lead acetate treatment significantly reduced the expression level of PGC-1α, but increased the level of MRP1 in mitochondria of TM4 cells. To determine the role of PGC-1α and MRP1 in lead acetate-induced mitochondrial toxicity, we then generated PGC-1α stable overexpression and MRP1 stable knockdown TM4 cells, respectively. The lead acetate treatment caused TM4 cell mitochondrial ultrastructure damages, a decrease in ATP synthesis, an increase in ROS levels, and apoptotic cell death. In contrast, stably overexpressing PGC-1α significantly ameliorated the lead acetate treatment-caused mitochondrial toxicity and apoptosis. Moreover, it was also found that stably knocking down the level of MRP1 increased the TM4 cell mitochondrial lead-accumulation by 4-6 folds. Together, the findings from this study suggest that PGC-1α and MRP1 plays important roles in protecting TM4 cells against lead-induced mitochondrial toxicity, providing a better understanding of lead-induced mitochondrial toxicity.

KW - Lead acetate

KW - MRP1

KW - Mitochondrial toxicity

KW - PGC-1α

KW - Sertoli cell

UR - http://www.scopus.com/inward/record.url?scp=84969626603&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84969626603&partnerID=8YFLogxK

U2 - 10.1016/j.tox.2016.05.016

DO - 10.1016/j.tox.2016.05.016

M3 - Article

C2 - 27236077

AN - SCOPUS:84969626603

SN - 0300-483X

VL - 355-356

SP - 39

EP - 48

JO - Toxicology

JF - Toxicology

ER -

The role of PGC-1α and MRP1 in lead-induced mitochondrial toxicity in testicular Sertoli cells

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this