Small Molecule Activators of Mitochondrial Fusion Prevent Congenital Heart Defects Induced by Maternal Diabetes

Area of Science:

• Developmental biology
• Mitochondrial biology
• Cardiovascular research

Background:

• Congenital heart defects (CHDs) are common birth defects, with nongenetic factors playing a significant role.
• The precise mechanisms by which nongenetic factors induce CHDs remain largely unknown.
• Maternal diabetes is a known risk factor for CHDs, but its underlying molecular pathways are not fully elucidated.

Purpose of the Study:

• To investigate if impaired mitochondrial fusion contributes to CHDs in the context of maternal diabetes.
• To evaluate the potential of mitochondrial fusion activators, teriflunomide and echinacoside, in mitigating CHDs during diabetic pregnancy.

Main Methods:

• Utilized a mouse model of diabetic pregnancy.
• Analyzed the expression of key regulatory molecules (FoxO3a, microRNAs) and mitochondrial fusion proteins (Mfn1, Mfn2).
• Assessed the incidence of CHDs in offspring and the effects of teriflunomide and echinacoside treatment.

Main Results:

• Maternal diabetes led to the activation of FoxO3a, which increased miR-140 and miR-195 expression.
• Elevated miR-140 and miR-195 suppressed the expression of Mfn1 and Mfn2, crucial for mitochondrial fusion.
• This suppression resulted in mitochondrial fusion defects and a higher incidence of CHDs in offspring.
• Treatment with teriflunomide and echinacoside effectively reduced CHD incidence in diabetic pregnancies.

Conclusions:

• Impaired mitochondrial fusion, driven by the FoxO3a/miR-140/miR-195 pathway, is a key mechanism in maternal diabetes-induced CHDs.
• Teriflunomide and echinacoside demonstrate therapeutic potential for preventing CHDs in pregnancies complicated by diabetes.