Autophagy and apoptosis, as major modes of cell death, play critical roles in cellular homeostasis. Our previous study demonstrated that the cross-talk between autophagy and apoptosis regulated cadmium-induced testicular injury and self-recovery, influencing male fertility. However, the underlying mechanism remains blurry. Herein, our subfertility rat model indicated that cadmium-induced autophagy and apoptosis were ameliorated by the activation of SIRT3 and blunted by the inhibition of SIRT3 in rat testis. Further, generating SIRT3 overexpression and knockdown models in TM3 mouse Leydig cells, we found that melatonin (SIRT3 activator) and overexpression of SIRT3 rescued cadmium-induced autophagy and apoptosis in TM3 cells. Knockdown of SIRT3 induced autophagy and apoptosis, which failed to be reversed by melatonin in TM3 cells. Taken together, SIRT3 functions as a pivotal protective factor in testicular Leydig cells injury, and melatonin regulates the cross-talk between autophagy and apoptosis by SIRT3, ameliorating cadmium-induced testicular injury.
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