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1-Nitropyrene disrupts testosterone biogenesis via AKAP1 degradation promoted mitochondrial fission in mouse Leydig
Wei-Wei Zhang1, Xiu-Liang Li1, Yu-Lin Liu1
1Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes & Department of Toxicology, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui Province, China.
Abstract:
Previous study found 1-NP disrupted steroidogenesis in mouse testis, but the underlying mechanism remained elusive. The current work aims to explore the roles of ROS-promoted AKAP1 degradation and excessive mitochondrial fission in 1-NP-induced steroidogenesis disruption in MLTC-1 cells. Transmission electron microscope analysis found 1-NP promoted excessive mitochondrial fission. Further data showed 1-NP disrupted mitochondrial function. pDRP1 (Ser637), a negative regulator of mitochondrial fission, was reduced in 1-NP-treated MLTC-1 cells. Mechanistically, 1-NP caused degradation of AKAP1, an upstream regulator of pDRP1 (Ser637). MG132, a proteasome inhibitor, attenuated 1-NP-induced AKAP1 degradation and downstream pDRP1 (Ser637) reduction, thereby ameliorating 1-NP-downregulated steroidogenesis. Further analysis found that cellular ROS was elevated and NOX4, HO-1 and SOD2 were upregulated in 1-NP-exposed MLTC-1 cells. NAC, a well-known commercial antioxidant, alleviated 1-NP-induced excessive ROS and oxidative stress. 1-NP-induced AKAP1 degradation and subsequent downregulation of pDRP1 (Ser637) were prevented by NAC pretreatment. Moreover, NAC attenuated 1-NP-resulted T synthesis disturbance in MLTC-1 cells. The present study indicates that ROS mediated AKAP1 degradation and subsequent pDRP1 (Ser637) dependent mitochondrial fission is indispensable in 1-NP caused T synthesis disruption. This study provides a new insight into 1-NP-induced endocrine disruption, and offers theoretical basis in public health prevention.
Insights
1-Naphthylpyrazole (1-NP) disrupts testosterone synthesis by promoting ROS-mediated AKAP1 degradation, leading to mitochondrial fission and impaired steroidogenesis in MLTC-1 cells.
Area of Science:
- Endocrinology
- Toxicology
- Cell Biology
Background:
- 1-Naphthylpyrazole (1-NP) is known to disrupt steroidogenesis, but the precise mechanisms are unclear.
- Understanding the molecular pathways involved in 1-NP-induced endocrine disruption is crucial for public health.
Purpose of the Study:
- To investigate the roles of reactive oxygen species (ROS)-promoted AKAP1 degradation and excessive mitochondrial fission in 1-NP-induced steroidogenesis disruption.
- To elucidate the mechanism by which 1-NP affects testosterone (T) synthesis in MLTC-1 cells.
Main Methods:
- Transmission electron microscopy to analyze mitochondrial morphology.
- Western blotting to assess protein levels (e.g., pDRP1, AKAP1).
- Cellular assays to measure ROS levels, mitochondrial function, and T synthesis.
- Treatment with antioxidants (NAC) and proteasome inhibitors (MG132).
Main Results:
- 1-NP induced excessive mitochondrial fission and disrupted mitochondrial function.
- 1-NP treatment led to AKAP1 degradation and reduced pDRP1 (Ser637) levels, linked to increased ROS.
- NAC treatment reversed 1-NP-induced ROS elevation, AKAP1 degradation, and T synthesis impairment.
Conclusions:
- ROS-mediated AKAP1 degradation and subsequent pDRP1 (Ser637)-dependent mitochondrial fission are critical in 1-NP-induced disruption of T synthesis.
- This study provides novel insights into the endocrine-disrupting effects of 1-NP and its mechanism.
- Findings offer a theoretical basis for public health strategies against 1-NP exposure.
