Targeted Deletion of Mitofusin 1 and Mitofusin 2 Causes Female Infertility and Loss of Follicular Reserve

Mitochondria are dynamic organelles that regulate their size, shape, and morphology through mechanisms called fusion and fission, to continually adapt themselves to their bioenergetic environment. These mechanisms play a critical role to maintain the mitochondrial function under metabolic and environmental stress. Mitofusin 1 (MFN1) and mitofusin 2 (MFN2) are transmembrane GTPases that regulate mitochondrial fusion mechanism and are required for the maintenance of cellular homeostasis. In this study, we aimed to determine the role of mitofusins in female reproductive competence and senescence using a mouse model with oocyte-specific double deletion of Mfn1 and Mfn2, eliminating the potential functional redundancy of these two proteins. Oocyte-specific targeted double deletion of Mfn1 and Mfn2 in mice resulted in female infertility associated with impaired follicular development and oocyte maturation. It also resulted in altered mitochondrial dynamics and mitochondrial dysfunction. Lack of Mfn1 and Mfn2 in oocytes resulted in accelerated follicular depletion and impaired oocyte quality which are consistent with phenotype of reproductive aging.