Diabetic pregnancy and maternal high-fat diet impair mitochondrial dynamism in the developing fetal rat heart by sex-specific mechanisms

Tricia D. Larsen, Kyle H. Sabey, Alexis J. Knutson, Tyler C.T. Gandy, Eli J. Louwagie, Lothar Lauterboeck, Kennedy S. Mdaki, Michelle L. Baack

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Infants born to diabetic or obese mothers are at greater risk of heart disease at birth and throughout life, but prevention is hindered because underlying mechanisms remain poorly understood. Using a rat model, we showed that prenatal exposure to maternal diabetes and a high-fat diet caused diastolic and systolic dysfunction, myocardial lipid accumulation, decreased respiratory capacity, and oxidative stress in newborn offspring hearts. This study aimed to determine whether mitochondrial dynamism played a role. Using confocal live-cell imaging, we examined mitochondrial dynamics in neonatal rat cardiomyocytes (NRCM) from four prenatally exposed groups: Controls, diabetes, high-fat diet, and combination exposed. Cardiac expression of dynamism-related genes and proteins were compared, and gender-specific differences were evaluated. Findings show that normal NRCM have highly dynamic mitochondria with a well-balanced number of fusion and fission events. Prenatal exposure to diabetes or a high-fat diet impaired dynamism resulting in shorter, wider mitochondria. Mechanisms of impaired dynamism were gender-specific and protein regulated. Females had higher expression of fusion proteins which may confer a cardioprotective effect. Prenatally exposed male hearts had post-translational modifications known to impair dynamism and influence mitophagy-mediated cell death. This study identifies mitochondrial fusion and fission proteins as targetable, pathogenic regulators of heart health in offspring exposed to excess circulating maternal fuels.

Original languageEnglish (US)
Article number3090
JournalInternational journal of molecular sciences
Volume20
Issue number12
DOIs
StatePublished - Jun 2 2019

Keywords

  • Cardiovascular disease
  • Maternal diabetes
  • Maternal high-fat diet
  • Mitochondrial dynamism
  • Sex-specific mechanisms of the developmental origins of health and disease (DOHaD)

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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