Mitochondrial miRNAs (mitomiRs): Plausible key players of metabolic stress induced sub-fertility in high yielding cows

Contact: Vijaya Simha Baddela, Ph.D.

Duration: 2020-2023

Funding: Deutsche Forschungsgemeinschaft, DFG BA 6909/1-1

It is well known that post-partum negative energy balance (NEB) can lead to anestrous and impaired cyclicity in dairy cows. Elevated concentrations of non-esterified fatty acids (NEFA), in serum and follicular fluid, are a well-characterized consequence of NEB. It has been shown that NEFA affects the function and viability of granulosa cells (GCs), which are key estradiol producing cells of the female reproductive system. However, the molecular mechanism of NEB induced granulosa cell dysfunction is not yet clearly understood in any species. Mitochondria, being the centers of fatty acid oxidation, show altered function under NEB conditions in granulosa cells. Emerging studies in cell biology have identified that mitochondrial microRNAs, called mitomiRs, regulate gene expression processes in mitochondria and thereby modulate cell health and function in different physiological conditions. In line with this, our preliminary experiments also showed that mitomiRs could determine the key functions such as oxidative phosphorylation and steroidogenesis in granulosa lutein cells. Therefore we believe that elevated concentrations of NEFA create disturbances in mitochondrial homeostasis by altering the mitomiR profile. The resulting mitomiRs could regulate the gene expression processes in mitochondria and thereby induce GC dysfunction. Accordingly, the global hypothesis to be addressed in the proposed project is that “Metabolic stress could alter GC mitomiR profiles, which in turn play a key role in GC dysfunction and apoptosis through regulating gene expression processes in mitochondria”. We plan to profile mitomiRs in GCs in vivo and in vitro under normal and metabolic stress conditions followed by functional characterization of the commonly regulated mitomiRs using advanced molecular methods, necessary to establish the role of mitomiRs in GCs. In addition, we will systematically investigate whether NEFA induced GC dysfunction can be reversed using exogenous mitomiR mimics and sponges. Delineating this novel regulation of mitomiRs would open a new dimension to our understanding of ovarian function under different pathophysiological conditions. The data to be generated in the project will further pave the way for future studies on mitomiRs in GCs.