Abstract

Background The incidence of reproductive system disorders has been steadily rising in recent years. Moreover, with the rising standard of living, the incidence of metabolic diseases also has been gradually increasing. However, the connection and mechanisms linking reproductive and metabolic diseases are poorly defined. Methods For organelle connectivity analysis, we analyzed mitochondria–endoplasmic reticulum (ER) contacts (MERCs) gene expression using a published single-cell RNA sequencing data. The link between lipid droplets (LDs) and actin cytoskeleton was analyzed by mass-spectrometry-based proteomics. By flow-cytometry-based cell sorting coupled with transmission electron microscopy, we explored the LD-mediated mitochondria–endoplasmic reticulum contacts. Results We found decreased expression of numerous MERC-associated genes, along with a reduction in Leydig cells (LCs), in high-fat diet (HFD) mice. Mechanistically, LDs downregulated the expression of G-actin, leading to the separation of mitochondria from the ER. From a functional perspective, Firsocostat, a lipogenesis enzyme acetyl-CoA carboxylase (ACC) inhibitor, inhibited LD synthesis, which shortened the distance between mitochondria and the ER, improved their functions, and promoted testosterone synthesis. Finally, targeting the LDs offered a promising therapeutic strategy to improve LC function under high-fat conditions, thereby protecting testicular endocrine function. Conclusions HFD leads to reproductive dysfunction by disrupting lipid-droplet-mediated Mito–ER contacts. Graphical abstract The alternative text for this image may have been generated using AI.