Targeting trophoblast cell mitochondrial dysfunction in preeclampsia via drug repurposing

Area of Science:

• Reproductive Biology
• Mitochondrial Biology
• Pharmacology

Background:

• Preeclampsia is a pregnancy disorder marked by hypertension and organ damage.
• Mitochondrial dysfunction is a key factor in preeclampsia, leading to placental issues and oxidative stress.

Purpose of the Study:

• To investigate the mechanisms of mitochondrial dysfunction in first-trimester trophoblast cells.
• To evaluate the therapeutic potential of aspirin, metformin, resveratrol, and AD-01 in improving trophoblast mitochondrial health.

Main Methods:

• Developed a 2D in vitro model of first-trimester trophoblasts to simulate preeclampsia conditions (hypoxia, mitochondrial dysfunction, inflammation).
• Treated cells with metformin, resveratrol, AD-01, or aspirin under preeclampsia-mimicking stimuli.
• Assessed mitochondrial dynamics using immunofluorescence, Seahorse XF Mito Stress Test, and RT-qPCR for key gene expression (mfn1, dnm1l, atg5, map1lc3b).

Main Results:

• Preeclampsia stimuli significantly altered mitochondrial networks, reducing size and number while increasing circularity.
• Metformin improved mitochondrial architecture under inflammation and normalized key gene expression and bioenergetics.
• Aspirin enhanced mitochondrial morphology under hypoxia; resveratrol and AD-01 demonstrated context-dependent protective effects.

Conclusions:

• Hypoxia, inflammation, and mitochondrial dysfunction are critical contributors to preeclampsia pathology.
• Aspirin, metformin, resveratrol, and AD-01 represent promising therapeutic strategies for improving mitochondrial health in preeclampsia.
• Targeted interventions could enhance mitochondrial function and improve pregnancy outcomes for women with preeclampsia.