BMI1 promotes steroidogenesis through maintaining redox homeostasis in mouse MLTC-1 and primary Leydig cells

Tingting Gao; Meng Lin; Binbin Shao; Qiao Zhou; Yufeng Wang; Xia Chen; Dan Zhao; Xiuliang Dai; Cong Shen; Hongbo Cheng; Shenmin Yang; Hong Li; Bo Zheng; Xingming Zhong; Jun Yu; Li Chen; Xiaoyan Huang

doi:10.1080/15384101.2020.1779471

BMI1 promotes steroidogenesis through maintaining redox homeostasis in mouse MLTC-1 and primary Leydig cells

Cell Cycle. 2020 Aug;19(15):1884-1898. doi: 10.1080/15384101.2020.1779471. Epub 2020 Jun 28.

Authors

Tingting Gao¹, Meng Lin², Binbin Shao³, Qiao Zhou⁴, Yufeng Wang¹, Xia Chen⁵, Dan Zhao⁶, Xiuliang Dai¹, Cong Shen⁷, Hongbo Cheng⁷, Shenmin Yang⁷, Hong Li⁷, Bo Zheng^{7

8}, Xingming Zhong^{9

10

11}, Jun Yu⁵, Li Chen¹, Xiaoyan Huang²

Affiliations

¹ Center of Clinical Reproductive Medicine, The Affiliated Changzhou Matemity and Child Health Care Hospital of Nanjing Medical University , Changzhou, China.
² State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University , Nanjing, China.
³ Department of Prenatal Diagnosis, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital , Nanjing, China.
⁴ Department of Reproduction, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital , Nanjing, China.
⁵ Department of Obstetrics and Gynecology, Affiliated Hospital of Jiangsu University, Jiangsu University , Zhenjiang, China.
⁶ Fourth Affiliated Hospital of Jiangsu University , Zhenjiang, China.
⁷ Center for Reproduction and Genetics, NHC Key Laboratory of Male Reproduction and Genetics, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University , Suzhou, China.
⁸ State Key Laboratory of Reproductive Medicine, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University , Suzhou, China.
⁹ NHC Key Laboratory of Male Reproduction and Genetics , Guangdong, China.
¹⁰ Department of Reproductive Immunity and Genetics, Family Planning Research Institute of Guangdong Province , Guangdong, China.
¹¹ Department of Reproductive Immunity and Genetics, Family Planning Special Hospital of Guangdong Province , Guangzhou, China.

Abstract

In males, aging is accompanied by decline in serum testosterone levels due to impairment of testicular Leydig cells. The polycomb protein BMI1 has recently been identified as an anti-aging factor. In our previous study, BMI1 null mice showed decreased serum testosterone and Leydig cell population, excessive oxidative stress and p16/p19 signaling activation. However, a cause-and-effect relationship between phenotypes and pathways was not investigated. Here, we used the rescue approach to study the role of oxidative stress or p16/p19 in BMI1-mediated steroidogenesis. Our results revealed that treatment with antioxidant NAC, but not down-regulation of p16/p19, largely rescued cell senescence, DNA damage and steroidogenesis in BMI1-deficient mouse MLTC-1 and primary Leydig cells. Collectively, our study demonstrates that BMI1 orchestrates steroidogenesis mainly through maintaining redox homeostasis, and thus, BMI1 may be a novel and potential therapeutic target for treatment of hypogonadism.

Keywords: BMI1; Leydig cells; oxidative stress; p16/p19 signaling; steroidogenesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylcysteine / pharmacology
Animals
Antioxidants / pharmacology
Apoptosis / drug effects
Cell Cycle / drug effects
Cell Proliferation / drug effects
Cell Survival / drug effects
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p16 / metabolism
Cyclin-Dependent Kinase Inhibitor p19 / metabolism
Heterocyclic Compounds, 2-Ring / pharmacology
Homeostasis* / drug effects
Leydig Cells / drug effects
Leydig Cells / metabolism*
Male
Mice
Models, Biological
Oxidation-Reduction / drug effects
Oxidative Stress / drug effects
Polycomb Repressive Complex 1 / metabolism*
Proto-Oncogene Proteins / metabolism*
Reactive Oxygen Species / metabolism
Signal Transduction / drug effects
Steroids / biosynthesis*
Testis / metabolism
Testosterone / biosynthesis
Thiazoles / pharmacology

Substances

Antioxidants
Bmi1 protein, mouse
Cdkn2d protein, mouse
Cyclin-Dependent Kinase Inhibitor p16
Cyclin-Dependent Kinase Inhibitor p19
Heterocyclic Compounds, 2-Ring
PTC-209
Proto-Oncogene Proteins
Reactive Oxygen Species
Steroids
Thiazoles
Testosterone
Polycomb Repressive Complex 1
Acetylcysteine

Grants and funding

This work was supported by National Natural Science Foundation of China [81901532 and 81901533]; Natural Science Foundation of Jiangsu Province [BK20190188]; Suzhou Science and Technology Development Plan [SYSD2019208]; Suzhou Introduced Project of Clinical Medical Expert Team [SZYJTD201708]; Suzhou Key Laboratory of Male Reproduction Research [SZS201718]; open project of NHC Key Laboratory of Male Reproduction and Genetics [KF201904] Science and Technology Project of Changzhou [CJ20180040]; and Yong Talents Training Program of Jiangsu University [5521470000].