Mitochondrial transfer improves cardiomyocyte bioenergetics and viability in male rats exposed to pregestational diabetes

Eli J. Louwagie, Tricia D. Larsen, Angela L. Wachal, Tyler C.T. Gandy, Michelle L. Baack

Research output: Contribution to journalArticlepeer-review

Abstract

Offspring born to diabetic or obese mothers have a higher lifetime risk of heart disease. Previously, we found that rat offspring exposed to late-gestational diabetes mellitus (LGDM) and maternal high-fat (HF) diet develop mitochondrial dysfunction, impaired cardiomyocyte bioener-getics, and cardiac dysfunction at birth and again during aging. Here, we compared echocardiog-raphy, cardiomyocyte bioenergetics, oxidative damage, and mitochondria-mediated cell death among control, pregestational diabetes mellitus (PGDM)-exposed, HF-diet-exposed, and combina-tion-exposed newborn offspring. We hypothesized that PGDM exposure, similar to LGDM, causes mitochondrial dysfunction to play a central, pathogenic role in neonatal cardiomyopathy. We found that PGDM-exposed offspring, similar to LGDM-exposed offspring, have cardiac dysfunction at birth, but their isolated cardiomyocytes have seemingly less bioenergetics impairment. This finding was due to confounding by impaired viability related to poorer ATP generation, more lipid perox-idation, and faster apoptosis under metabolic stress. To mechanistically isolate and test the role of mitochondria, we transferred mitochondria from normal rat myocardium to control and exposed neonatal rat cardiomyocytes. As expected, transfer provides a respiratory boost to cardiomyocytes from all groups. They also reduce apoptosis in PGDM-exposed males, but not in females. Findings highlight sex-specific differences in mitochondria-mediated mechanisms of developmentally programmed heart disease and underscore potential caveats of therapeutic mitochondrial transfer.

Original languageEnglish (US)
Article number2382
Pages (from-to)1-21
Number of pages21
JournalInternational journal of molecular sciences
Volume22
Issue number5
DOIs
StatePublished - Mar 1 2021
Externally publishedYes

Keywords

  • Developmentally programmed heart disease
  • Diabetic pregnancy
  • Mito-chondrial transfer
  • Mitochondria

ASJC Scopus subject areas

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

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