Coq4 deficiency induces placental vascular development defects through FSP1/CoQ10 axis-mediated endothelial...

Coenzyme Q10 (CoQ10), a critical electron carrier in mitochondrial respiratory chains, is essential for cellular energy metabolism. Ubiquinone biosynthesis protein 4 homolog (Coq4), a rate-limiting enzyme in CoQ10 biosynthesis, is indispensable for embryonic development. However, the mechanisms underlying Coq4 deficiency-induced developmental defects remain elusive. Emerging evidence highlights the FSP1/CoQ10 axis as a central regulator of lipid peroxidation and ferroptosis, a non-apoptotic cell death mechanism implicated in placental vascular dysgenesis and trophoblast dysfunction. This study aims to elucidate the molecular mechanisms by which Coq4 deficiency disrupts placental development, with a focus on the interplay between the FSP1/CoQ10 axis and endothelial ferroptosis.

Coq4^+/- mice were generated via CRISPR-Cas9-mediated genome editing. Offspring were genotyped by Polymerase Chain Reaction (PCR), and placental tissues were collected at E9.5 for histological analysis and immunofluorescence. Lentivirus-mediated Coq4 knockdown in human umbilical vein endothelial cells (HUVECs) was combined with RNA sequencing (RNA-seq) to identify differentially expressed genes. Key pathway proteins were validated by Western blotting.

Coq4^-/- embryos exhibited embryonic lethality and the placentas showed vascular rarefaction and impaired trophoblast invasion. Transcriptomic profiling and Western blotting identified upregulated ferroptosis-related genes including acyl-CoA synthase long-chain family member 4 (ACSL4), ferritin heavy chain 1(FTH1) and downregulated Ferroptosis Suppressor Protein 1(FSP1), but without changes observed on the glutathione peroxidase 4 (GPX4). FSP1 overexpression or CoQ10 supplementation alone partially alleviates ferroptosis whereas combined intervention more effectively improves it.

This study demonstrates that Coq4 deficiency induces endothelial ferroptosis via disrupting the FSP1-CoQ10 antioxidant axis, and may also provide new insights into the pathogenesis of pregnancy complications caused by placental dysfunction and iron-related vascular diseases, while offering novel approaches for exploring potential therapeutic targets.