SIRT2 alleviates pre-eclampsia via prompting mitochondrial biogenesis and function

Area of Science:

• Obstetrics and Gynecology
• Mitochondrial Biology
• Cellular Physiology

Background:

• Pre-eclampsia (PE) affects 2-8% of pregnancies globally, contributing to maternal and neonatal morbidity/mortality.
• Mitochondrial dysfunction and impaired trophoblast cell motility are implicated in PE pathogenesis.
• Reduced expression of mitochondrial biogenesis proteins (PGC1α, NRF1, TFAM) and SIRT2 has been observed in PE.

Purpose of the Study:

• To investigate the regulatory role of SIRT2 in PGC1α expression and acetylation.
• To determine the influence of SIRT2 on trophoblast cell migration and invasion in PE.
• To elucidate the impact of SIRT2 on mitochondrial biogenesis and function in PE.

Main Methods:

• Protein expression analysis of SIRT2, PGC1α, NRF1, and TFAM in placental tissues from PE patients and controls.
• In vitro studies in trophoblast cells to assess SIRT2's effect on mitochondrial biogenesis, morphology, and function.
• In vivo validation in lipopolysaccharide (LPS)-induced PE mice using an adeno-associated virus transfection system.

Main Results:

• PE patients and mice exhibited lower SIRT2 and PGC1α/NRF1/TFAM protein levels and mitochondrial dysfunction.
• SIRT2 overexpression increased PGC1α expression, promoted PGC1α deacetylation, and enhanced trophoblast cell mitochondrial function and motility.
• In vivo, SIRT2 overexpression ameliorated PE-like symptoms and adverse pregnancy outcomes in LPS-induced PE mice by promoting mitochondrial biogenesis.

Conclusions:

• SIRT2 plays a crucial role in regulating PGC1α acetylation and mitochondrial biogenesis.
• SIRT2 may serve as a potential therapeutic target for pre-eclampsia.
• Improving SIRT2 activity could enhance mitochondrial function and counteract PE pathology.