Lin28a induced mitochondrial dysfunction in human granulosa cells via suppressing LARS2 expression

Granulosa cells surround the oocytes as a component of ovarian follicles and produce sex steroids and growth factors to support oocyte development. Mitochondria is one of the multiple factors regulating granulosa cell function by modulating bioenergetic pathways and maintaining cells' metabolic needs. Lin28a was reported to regulate the primordial germ cell development in the ovary and affect the fertility rate in females. However, whether Lin28a modulated mitochondria function in granulosa cells to regulate steroidogenesis remains a further exploration. In this study, we utilized immortal human granulosa cells (HGrC1) to overexpress or suppress the protein level of Lin28a. Results showed that overexpression of Lin28a could decrease the estrogen level, ATP content, mitochondrial membrane potential and Glutathione (GSH) level, while silencing Lin28a caused the opposite effect. Further, we found that overexpression of LARS2, a mitochondrial leucyl-tRNA synthetase, could increase the estrogen level, ATP content, mitochondrial membrane potential and GSH level while silencing LARS2 caused adverse results. Overexpression of LARS2 reversed Lin28a-induced estrogen downregulation and mitochondrial dysfunction. Moreover, overexpression of LARS2 increased the mRNA level of Pgc1 alpha and Nrf2, which were involved in mitochondrial biogenesis. Besides, Lin28a could directly bind to the mRNA of Lars2 to suppress its translation. Taken together, overexpression of Lin28a caused mitochondrial dysfunction in granulosa cells via suppressing LARS2 expression. This study can provide new insights into how Lin28a regulates mito-chondrial function in granulosa cells and influences female fertility.