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PINK1-mediated mitophagy induction protects against preeclampsia by decreasing ROS and trophoblast pyroptosis
1Department of Obstetrics & Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, PR China.
Insights
PTEN-induced putative kinase 1 (PINK1)-mediated mitophagy protects against preeclampsia (PE) by reducing inflammation and trophoblast pyroptosis. This pathway may be a therapeutic target for PE.
Area of Science:
- Reproductive biology
- Cellular and molecular pathology
- Immunology
Background:
- Preeclampsia (PE) is a serious pregnancy complication linked to placental inflammation.
- PTEN-induced putative kinase 1 (PINK1)-mediated mitophagy is involved in inflammation.
- Dysregulated mitophagy may contribute to PE pathogenesis by activating trophoblast pyroptosis.
Purpose of the Study:
- To investigate the role of PINK1-mediated mitophagy in preeclampsia (PE).
- To determine if PINK1 regulates trophoblast pyroptosis and reactive oxygen species (ROS) production in PE.
- To explore the potential of mitophagy as a therapeutic target for PE.
Main Methods:
- Mitochondrial morphology analysis via transmission electron microscopy.
- Immunohistochemistry to determine PINK1 localization in placental tissues.
- Western blotting and RT-qPCR to compare expression levels of mitophagy and pyroptosis markers between normal and PE placentae.
- In vitro studies using HTR-8/SVneo cells subjected to hypoxia/reoxygenation (H/R) and manipulated for PINK1 expression.
- Inhibition of ROS production using MitoTEMPO to assess its effect on PINK1 knockdown-induced pyroptosis.
Main Results:
- PE placentae showed accumulated swollen mitochondria and abolished PINK1-mediated mitophagy, alongside induced pyroptosis.
- H/R stimulation exacerbated mitophagy downregulation and pyroptosis upregulation.
- PINK1 overexpression reduced H/R-induced ROS and pyroptosis, while PINK1 silencing had the opposite effect.
- Inhibition of ROS production attenuated the pro-pyroptosis effect of PINK1 knockdown.
Conclusions:
- PINK1-mediated mitophagy plays a protective role in preeclampsia (PE).
- This protective effect is mediated by the reduction of reactive oxygen species (ROS) and trophoblast pyroptosis.
- Targeting PINK1-mediated mitophagy could be a potential therapeutic strategy for PE.
Introduction:
Preeclampsia (PE) is a multisystemic disorder attributed to the excessive presentation of placenta-derived immunoinflammatory factors. PTEN-induced putative kinase 1 (PINK1)-mediated mitophagy participates in the development and persistence of the inflammation. We hypothesized that dysregulated mitophagy might be involved in the pathogenesis of PE by promoting the activation of trophoblast pyroptosis that augment inflammation.
Methods:
The morphology of mitochondrial in placenta were observed by transmission electron microscopy. The localization of PINK1 in the placenta was determined by immunohistochemistry. The expression levels of PINK1, PARKIN, LC3B, and SQSTM1 and pyroptosis-related molecules were compared between normal pregnancies and PE. We used hypoxia/reoxygenation (H/R) to stimulate the trophoblast hypoxia environment. HTR-8/SVneo cells were transfected with PINK1 plasmid and si-PINK1, respectively, and then were treated with H/R, to determine whether PINK1 regulated ROS and HTR-8/Svneo pyroptosis. Finally, ROS production was inhibited by MitoTEMPO to observe whether the pro-pyroptosis effect of PINK1 knockdown is alleviated.
Results:
Swollen mitochondrial were accumulated in the PE placentae. PINK1 is localized on villus trophoblast (VTs) and extravillous trophoblast (EVTs). PINK1-mediated mitophagy was abolished in the PE placenta, while the levels of pyroptosis were induced. H/R stimulation aggravated the downregulation of mitophagy and the up-regulation of pyroptosis. Overexpression of PINK1 mitigated H/R-induced upregulation of ROS and pyroptosis while silencing PINK1 did the opposite. Reducing ROS production can effectively resist the pro-pyroptosis effect of PINK1 knockdown.
Discussion:
This study demonstrated that PINK1-mediated mitophagy might played a protective role in PE by reducing ROS and trophoblast pyroptosis.
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