RAB5A regulates cell proliferation and lipid metabolism by modulating mitochondrial ROS via AMPK signaling pathway in ovarian granulosa cells

Ovarian granulosa cells (GCs) play a crucial role in follicle development and hormone production. These functions require substantial energy, supported by mitochondrial activity and balanced lipid metabolism. RAB5 is known to maintain mitochondrial homeostasis; however, its role in regulating lipid metabolism via the energy-sensing AMP-activated protein kinase (AMPK) pathway remains unclear. In polycystic ovary syndrome (PCOS), a disorder often linked to metabolic and mitochondrial defects in GCs, RAB5A levels are significantly reduced in obese subtypes. In this study, we demonstrate that RAB5A deficiency disrupts lipid metabolism and impairs normal cell proliferation, characterized by increased mitochondrial stress (increased reactive oxygen species) and activation of mitophagy via AMPK. RAB5A may coordinate with MIGA2, a protein involved in regulating mitochondria-lipid droplet interactions, to modulate lipid metabolism via AMPK activity. Notably, activating AMPK with AICAR reverses the adverse effects of RAB5A loss. Collectively, these findings identify RAB5A as a key regulator of GC function and a potential therapeutic target in obese PCOS.