Mitochondrial and Glucose Metabolic Patterns in Pre‐Granulosa Cells and Oocytes and Their Dysfunctions Induce Impaired Primordial Follicle Formation in Mice

ABSTRACT In mammals, the establishment of primordial follicles (PFs) occurs in an orderly manner and is an energy‐demanding process. However, the mechanisms underlying the supply and demand of energy metabolism during primordial follicle formation, particularly glycolysis and oxidative phosphorylation (OXPHOS) signaling, remain poorly understand. Herein, based on the analyses of single‐cell RNA sequencing (scRNA‐seq) data from mouse ovarian tissues, gene expression associated with glycolysis and OXPHOS signaling were dynamically changed along pseudotime trajectory in pre‐granulosa (PG) cells and oocytes following cell development and PF formation. The molecules related to glycolysis and OXPHOS signaling exhibited dynamic expression patterns in mouse ovarian tissues following PF formation, with distinct expression levels and location in somatic cells and oocytes. The dysfunctions of mitochondrial and glucose metabolic patterns using glycolysis inhibitor (2‐Deoxy‐Dglucose, 2‐DG) or OXPHOS signaling inhibitor (metformin, MET) significantly inhibited PF formation, disordered oocyte development, downregulated key gene expression, impaired the recruitment and maintenance of PG cells, and altered cell proliferation and apoptosis. Collectively, these results demonstrate that cellular metabolic patterns are diverse and dynamically regulate in oocytes and PG cells during PF formation of mice, and glucose metabolism is essential for PF formation and its disruption inhibits PF formation.