Graduation Year
2024
Document Type
Master's Thesis
Degree
Master of Science
Program
Biological Science
Program Director
Meredith Protas, PhD
First Reader
Olga Bielska, PhD
Second Reader
Genesis Vega Hormazabal, PhD
Abstract
Age-related decline in ovarian follicles and oocyte quantity and quality is a pivotal factor contributing to female infertility, yet the underlying mechanisms remain elusive. Mitochondrial fission factor (MFF), a critical regulator of mitochondrial division, has emerged as a key player in this context. Previous studies, including our own, have unveiled an age-related decline in MFF protein levels in multiple organs across species, suggesting its potential involvement in reproductive aging. Concurrently, Pumilio RNA binding family member 2 (PUM2) has emerged as a key player in modulating MFF protein production by interacting with its mRNA.
Recently, our lab discovered MFF’s role in aging and found that MFF knockout (KO) mice showed an accelerated aging phenotype with a severely shortened lifespan. Additionally, MFF KO male and female mice are infertile compared to their age matched wild type (WT) littermates. Given these findings, in this study, we focused on investigating the role of MFF loss on female and male reproduction using a murine model. We have systematically studied both internal and external reproductive anatomy, along with the morphology and physiology of reproductive organs in MFF KO mice compared to wild type (WT) littermates. We also explored MFF protein expression levels across different estrous stages in mouse ovaries and analyzed luteinizing hormone (LH) gonadotropin levels in the plasma of MFF KO mice.
Our results revealed significant decreases in MFF protein levels in aged ovaries, while levels remained constant across estrous stages in young ovaries. Both male and female MFF KO mice exhibited markedly smaller reproductive organs compared to their wild type counterparts. Additionally, they manifested significant delays in puberty onset. Notably, female MFF KO mice lacked estrous cyclicity, a phenomenon correlated with reduced levels of LH in these animals. A histological analysis coupled with quantification confirmed that MFF KO female mice did not display any corpora lutea, corroborating our previous findings of anovulatory phenotype in MFF KO female mice. This research has significantly enhanced our comprehension of the roles played by MFF molecular pathway in mouse reproduction,particularly in female fertility and aging Moreover, it holds promise for contributing to the development of innovative therapeutic interventions aimed at treating infertility.