The Remodeling of Mitochondrial-Endoplasmic Reticulum Contacts by Omega-3 Fatty Acids Mitigates Dietary Advanced Glycation End Product-Driven Sertoli Cell Senescence and Oligoasthenozoospermia

Dietary components or patterns have been shown to affect male fertility. The increasing intake of processed foods rich in advanced glycation end products (AGEs) may threaten spermatogenesis. However, the key cell type affected by AGEs in spermatogenic microenvironment remains unspecified. Furthermore, given that subcellular organelle interactions, particularly communications between mitochondria and endoplasmic reticulum (ER), are of paramount importance in male fertility, it is worthwhile to investigate dynamic changes of mitochondria-ER contacts (MERCs) in AGE-driven spermatogenesis dysfunction. In this study, we found that serum AGEs levels increased in patients with oligoasthenozoospermia (OAZ), which was accompanied by decreased inhibin B levels, leading us to explore the effect of AGEs on Sertoli cells. <i>In vivo</i> experiments revealed that AGEs-rich diet disrupted spermatogenesis and induced Sertoli cell senescence and dysfunction in mice. We further confirmed that AGEs elicited an increase in MERCs, as well as ER stress and mitochondrial dysfunction in Sertoli cells. Omega-3 polyunsaturated fatty acids (omega-3), which are a category of dietary supplements with the potential to improve male fertility, were employed in the rescue experiment. We demonstrated that omega-3 mitigate dietary AGE-induced Sertoli cell senescence and OAZ via the remodeling of MERCs, highlighting the AGE-RAGE axis as a potential target for treating male infertility.