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Triptolide Induces Leydig Cell Apoptosis by Disrupting Mitochondrial Dynamics in Rats
Linyan Lv1, Yajie Chang1, Yanqing Li1
1Reproductive Medicine Research Center, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
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.
Insights
Triptolide causes male reproductive toxicity by inducing Leydig cell apoptosis via mitochondrial pathways. Inhibiting dynamin-related protein 1 (Drp1) may offer a protective strategy against this toxicity.
Area of Science:
- Reproductive toxicology
- Mitochondrial biology
- Cellular apoptosis
Background:
- Triptolide is clinically used but causes male reproductive toxicity.
- The mechanisms underlying triptolide's reproductive toxicity are not fully understood.
- Potential intervention targets for mitigating triptolide's side effects are needed.
Purpose of the Study:
- To investigate the mechanism of triptolide-induced testicular Leydig cell apoptosis.
- To identify potential therapeutic targets for triptolide's reproductive toxicity.
Main Methods:
- Triptolide treatment of rat testicular Leydig cells in vitro and in vivo.
- Analysis of mitochondrial apoptosis pathway activation.
- Assessment of dynamin-related protein 1 (Drp1) expression and mitochondrial dynamics.
- Evaluation of Mdivi-1, a Drp1 inhibitor, as a potential intervention.
Main Results:
- Triptolide induced apoptosis in rat testicular Leydig cells via the mitochondrial pathway.
- Triptolide caused hypoleydigism and impaired spermatogenesis in vivo.
- Triptolide upregulated Drp1, disrupting mitochondrial dynamics and activating apoptosis.
- Mdivi-1 partially reversed triptolide-induced mitochondrial dysfunction and Leydig cell apoptosis.
Conclusions:
- Triptolide induces male reproductive toxicity by activating the mitochondrial apoptosis pathway in Leydig cells.
- Drp1 overexpression plays a key role in triptolide-induced mitochondrial dysfunction and apoptosis.
- Inhibiting Drp1 over-activation presents a potential strategy to mitigate triptolide's reproductive toxicity.
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