MRPL13 deficiency triggers trophoblast mitochondrial unfolded protein response in early-onset preeclampsia

This study investigated the critical role of mitochondrial dysfunction in early-onset preeclampsia (EOPE), a major contributor to perinatal morbidity and mortality. We enrolled 12 patients diagnosed with EOPE and 8 healthy control women. Placental trophoblasts from these participants underwent comprehensive proteomic sequencing to identify differentially expressed proteins between the two groups. Key findings from proteomics were rigorously cross-verified using western blotting and immunofluorescence techniques. To further elucidate the functional consequences, we utilized the human placental trophoblast cell lines HTR8/SVneo and BeWo, employing small interfering RNA to reduce the expression of a target protein gene, and subsequently observing its effects on mitochondrial function and overall trophoblast cell behavior. Our results revealed 280 differentially expressed proteins, with a notable downregulation of mitochondrial ribosomal proteins. Specifically, the expression of mitochondrial ribosomal proteins L13 (MRPL13) and MRPL9 was significantly decreased in the EOPE group, alongside a significant reduction in the mitochondrial unfolded protein response (UPRmt)-related protein caseinolytic protease P (CLPP). In in vivo experiments, we found that the UPRmt became more severe in HTR8/SVneo and BeWo with reducing MRPL13, leading to a significant inhibition of cell migration and an enhancement of autophagy. Specifically, under tunicamycin-induced endoplasmic reticulum stress, MRPL13-knockdown also depleted Heat shock protein 60 (HSP60) and CLPP, aggravated UPRmt, and promoted mitochondrial dysfunction. In conclusion, our findings suggest that downregulation of MRPL13 may induce mitochondrial dysfunction via participating in the UPRmt, thereby negatively impacting the migration, proliferation, and invasion of trophoblast cells, and contributing to the pathogenesis of EOPE.