Age and Sex Influence Mitochondria and Cardiac Health in Offspring Exposed to Maternal Glucolipotoxicity

Area of Science:

• Cardiovascular Biology
• Mitochondrial Medicine
• Developmental Programming

Background:

• Infants born to diabetic mothers face risks of congenital cardiomyopathy and adult myocardial infarction.
• The underlying mechanisms linking maternal diabetes to offspring cardiac dysfunction remain largely unknown.
• Previous work implicated maternal glucolipotoxicity and fuel-mediated mitochondrial dysfunction in neonatal rat heart issues.

Purpose of the Study:

• To investigate the long-term cardiometabolic consequences of prenatal exposure to maternal diabetes in adult offspring.
• To elucidate the role of mitochondrial function, turnover, and cell death in age- and sex-specific cardiac decline.

Main Methods:

• Cross-fostering of rat pups born to diabetic and control mothers.
• Longitudinal assessment using echocardiography, cardiomyocyte bioenergetics, and mitochondrial assessments.
• Analysis of mitochondrial turnover, mitophagy, and cell death pathways under metabolic stress in aged adults.

Main Results:

• Cardiac function, initially normal after weaning, declines in aged adult rats exposed prenatally to diabetes.
• Impaired oxidative phosphorylation, increased mitochondrial content, and higher oxygen consumption characterize affected aged hearts.
• Prenatal exposure leads to sex-specific mitochondrial defects in male cardiomyocytes, including impaired mitophagy and increased cell death under stress.

Conclusions:

• Developmental exposure to maternal diabetes results in lasting cardiometabolic deficits that manifest in aged adulthood.
• Mitochondrial dysfunction, including impaired oxidative phosphorylation and mitophagy, is a key mechanism driving heart disease.
• Age- and sex-specific mitochondrial alterations play a critical role in the developmental programming of adult heart disease.