Targeted antioxidant delivery modulates mitochondrial functions, ameliorates oxidative stress and preserve sperm quality during cryopreservation

Mitochondria are vital organelles with a multifaceted role in cellular bioenergetics, biosynthesis, signaling and calcium homeostasis. During oxidative phosphorylation, sperm mitochondria generate reactive oxygen species (ROS) at physiological levels mediating signaling pathways essential for sperm fertilizing competence. Moreover, sperm subpopulation with active mitochondria is positively associated with sperm motility, chromatin and plasma membrane integrity, and normal morphology. However, the osmotic and thermal stress, and intracellular ice crystal formation generate excess ROS to cause mitochondrial dysfunction, potentiating cryoprotectant-induced calcium overload in the mitochondrial matrix. It further stimulates the opening of mitochondrial permeability transition pores (mPTP) to release pro-apoptotic factors from mitochondria and initiate apoptotic cascade, with a decrease in Mitochondrial Membrane Potential (MMP) and altered sperm functions. To improve the male reproductive potential, it is essential to address challenges in semen cryopreservation, precisely the deleterious effects of oxidative stress on sperm quality. During semen cryopreservation, the supplementation of extended semen with conventional antioxidants is extensively reported. However, the outcomes of supplementation to improve semen quality are inconclusive across different species, which is chiefly attributed to the unknown bioavailability of antioxidants at the primary site of ROS generation, i.e., mitochondria. Increasing evidence suggests that the targeted delivery of antioxidants to sperm mitochondria is superior in mitigating oxidative stress and improving semen freezability than conventional antioxidants. Therefore, the present review comprehensively describes mitochondrial-targeted antioxidants, their mechanism of action and effects of supplementation on improving semen cryopreservation efficiency in different species. Moreover, it also discusses the significance of active mitochondria in determining sperm fertilizing competence, cryopreservation-induced oxidative stress and mitochondrial dysfunction, and its implications on sperm fertility. The potential of mitochondrial-targeted antioxidants to modulate mitochondrial functions and improve semen quality has been reviewed extensively.