Triptolide Induces Leydig Cell Apoptosis by Disrupting Mitochondrial Dynamics in Rats.

Linyan Lv,Min Zhang,Xing Yang,Jiahui Yao,Yajie Chang,Yun Xie,Xiaoyan Liang,Yanqing Li,Guihua Liu,Haicheng Chen

doi:10.3389/fphar.2021.616803

Abstract

Triptolide is widely used in the clinical treatment of various diseases. Side effects, including reproductive toxicity to male patients, limit its application. However, no detailed mechanisms or potential intervention targets have been reported. In this study, we show that triptolide activated the mitochondrial apoptosis pathway in rat testicular Leydig cells and induced apoptosis both in vivo and in vitro, which may cause hypoleydigism and impair spermatogenesis. Mechanistically, triptolide-induced dynamin-related protein 1 (Drp1) overexpression, which interfered with mitochondrial dynamic stability to activate the mitochondrial apoptosis pathway. Mdivi-1, a selective Drp1 inhibitor, partially reversed the mitochondrial dynamic disturbance and rat testicular Leydig cell apoptosis induced by triptolide. Inhibiting Drp1 over-activation may be a new strategy for mitigating the reproductive toxicity of triptolide.

Highlights

Triptolide (TP), an active compound from a Chinese herb, is widely used in the clinic to treat multiple diseases, including autoimmune diseases, cancers, and diabetic nephropathy
We found that triptolide reduced testicular weight and serum testosterone in rats and induced Leydig cell apoptosis, mitochondrial dysfunction and interstitial tissue damage by disrupting the dynamic balance of mitochondrial fission and fusion
Another study reported that triptolide induced Leydig cell apoptosis, and this effect might be highly associated with miR-200 (Miao et al, 2020)

Summary

INTRODUCTION

Triptolide (TP), an active compound from a Chinese herb, is widely used in the clinic to treat multiple diseases, including autoimmune diseases, cancers, and diabetic nephropathy. Mitochondrial fission and fusion maintain a dynamic balance to preserve normal mitochondrial function and adapt to environmental changes (Scott and Youle, 2010). Disruption of this balance leads to mitochondrial dysfunction, which occurs in various diseases (Mouli et al, 2009; Haun et al, 2013; Khacho et al, 2014). Aberrant Drp expression disrupts the balance of mitochondrial fission and fusion, causing various diseases, including Parkinson’s disease, pancreatic tumors, and Huntington’s disease We investigated triptolideinduced aberrant Drp expression in Leydig cells, which disrupted the dynamic balance of mitochondrial fission and fusion, damaged mitochondrial function and induced steroidogenesis impairment in vivo and in vitro

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DATA AVAILABILITY STATEMENT