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.

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].