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Background <p>Heat stress (HS) poses a significant threat to male goat reproduction. Sertoli cells (SCs) provide both structural and nutritional support necessary for germ cells. HS induces physiological and biochemical changes in SCs. Nevertheless, the molecular mechanisms involved are still not fully understood. Melatonin is a classic antioxidant that can alleviate HS-induced male reproductive damage. However, the underlying molecular mechanisms by which melatonin mitigates damage to goat testicular SCs remain unclear and require further investigation.</p> Results <p>In this study, an in vivo heat stress model was established in goats. The results showed that HS exposure led to testicular injury, abnormal spermatogenesis and apoptosis of SCs. To elucidate the mechanism of HS-induced SC apoptosis, primary SCs were isolated and cultured from goat testes, then exposed to HS. HS exposure increased the production of reactive oxygen species (ROS), decreased adenosine triphosphate (ATP) synthesis, and reduced mitochondrial membrane potential in SCs. Additionally, HS increased the expression of mitochondrial fission proteins 1 (FIS1) and dynamin-related protein 1 (DRP1) while decreasing the expression of mitochondrial fusion proteins Mitofusin 1 (MFN1), Mitofusin 2 (MFN2), and optic atrophy 1 (OPA1). This resulted in excessive mitochondrial fission and mitochondria-dependent apoptosis. Mdivi-1 (DRP1 inhibitor) reduces mitochondria-dependent apoptosis by inhibiting excessive mitochondrial fission. Mitochondrial fission is closely related to mitophagy. HS activated upstream mitophagy but inhibited autophagic flux, disrupting mitophagy and exacerbating mitochondria-dependent apoptosis. Finally, the classical antioxidant melatonin was shown to reduce mitochondria-dependent apoptosis in SCs exposed to HS by decreasing ROS levels, restoring mitochondrial homeostasis, and normalizing mitophagy.</p> Conclusions <p>In summary, these findings indicated that the mechanism of HS-induced mitochondria-dependent apoptosis in SCs is mediated by hyperactivation of the ROS-DRP1-mitochondrial fission axis and inhibition of mitochondrial autophagy. Melatonin inhibited HS-induced mitochondria-dependent apoptosis in SCs by restoring mitochondrial homeostasis. This study enhances the understanding of the mechanisms through which heat stress triggers apoptosis and provides a vision for the development of drugs against HS by targeting mitochondria in goats.</p> Graphical Abstract <p></p>

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ROS-DRP1-mediated excessive mitochondrial fission and autophagic flux inhibition contribute to heat stress-induced apoptosis in goat Sertoli cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月16日

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  • Fei Wen,
  • Jiajing Gao,
  • Guoyu Zhang,
  • Songmao Guo,
  • Xing Zhang,
  • Shuaiqi Han,
  • Xianzou Feng,
  • Xiaoxu Chen,
  • Jianhong Hu

摘要

Background

Heat stress (HS) poses a significant threat to male goat reproduction. Sertoli cells (SCs) provide both structural and nutritional support necessary for germ cells. HS induces physiological and biochemical changes in SCs. Nevertheless, the molecular mechanisms involved are still not fully understood. Melatonin is a classic antioxidant that can alleviate HS-induced male reproductive damage. However, the underlying molecular mechanisms by which melatonin mitigates damage to goat testicular SCs remain unclear and require further investigation.

Results

In this study, an in vivo heat stress model was established in goats. The results showed that HS exposure led to testicular injury, abnormal spermatogenesis and apoptosis of SCs. To elucidate the mechanism of HS-induced SC apoptosis, primary SCs were isolated and cultured from goat testes, then exposed to HS. HS exposure increased the production of reactive oxygen species (ROS), decreased adenosine triphosphate (ATP) synthesis, and reduced mitochondrial membrane potential in SCs. Additionally, HS increased the expression of mitochondrial fission proteins 1 (FIS1) and dynamin-related protein 1 (DRP1) while decreasing the expression of mitochondrial fusion proteins Mitofusin 1 (MFN1), Mitofusin 2 (MFN2), and optic atrophy 1 (OPA1). This resulted in excessive mitochondrial fission and mitochondria-dependent apoptosis. Mdivi-1 (DRP1 inhibitor) reduces mitochondria-dependent apoptosis by inhibiting excessive mitochondrial fission. Mitochondrial fission is closely related to mitophagy. HS activated upstream mitophagy but inhibited autophagic flux, disrupting mitophagy and exacerbating mitochondria-dependent apoptosis. Finally, the classical antioxidant melatonin was shown to reduce mitochondria-dependent apoptosis in SCs exposed to HS by decreasing ROS levels, restoring mitochondrial homeostasis, and normalizing mitophagy.

Conclusions

In summary, these findings indicated that the mechanism of HS-induced mitochondria-dependent apoptosis in SCs is mediated by hyperactivation of the ROS-DRP1-mitochondrial fission axis and inhibition of mitochondrial autophagy. Melatonin inhibited HS-induced mitochondria-dependent apoptosis in SCs by restoring mitochondrial homeostasis. This study enhances the understanding of the mechanisms through which heat stress triggers apoptosis and provides a vision for the development of drugs against HS by targeting mitochondria in goats.

Graphical Abstract