MFN2 Plays a Distinct Role from MFN1 in Regulating Spermatogonial Differentiation

Although mitochondrial morphology is well-known for its role in cellular homeostasis, there is surprisingly little knowledge on whether mitochondrial remodeling is required for postnatal germ cell development. In this study, we investigated the functions of MFN1 and MFN2, two GTPases in mitochondrial fusion, during early spermatogenesis. We observed increased MFN expressions along with increased mitochondrial and endoplasmic reticulum (ER) activities during spermatogonial differentiation. Deletion of either Mfn led to DNA oxidation and apoptosis specifically in differentiating spermatogonia and spermatocytes, which in turn caused male infertility. We further found MFN2 regulated spermatogenesis by modulating both mitochondrial and ER functions, a mechanism distinct from that of MFN1. Defects of germ cell development in MFN2 mutants were corrected by MFN2 at either mitochondria or ER but not by MFN1. Our study thus reveals an essential requirement of MFN-mediated mitochondrial and ER coordination in spermatogenesis, providing critical insights into mitochondrial determinants of male fertility.