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

Eli J Louwagie; Tricia D Larsen; Angela L Wachal; Tyler C T Gandy; Julie A Eclov; Todd C Rideout; Katherine A Kern; Jacob T Cain; Ruthellen H Anderson; Kennedy S Mdaki; Michelle L Baack

doi:10.1016/j.isci.2020.101746

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

iScience. 2020 Oct 28;23(11):101746. doi: 10.1016/j.isci.2020.101746. eCollection 2020 Nov 20.

Authors

Eli J Louwagie^{1

2}, Tricia D Larsen², Angela L Wachal², Tyler C T Gandy², Julie A Eclov², Todd C Rideout³, Katherine A Kern³, Jacob T Cain², Ruthellen H Anderson^{1

2}, Kennedy S Mdaki², Michelle L Baack^{1

2

4}

Affiliations

¹ University of South Dakota Sanford School of Medicine, Sioux Falls, SD 57105, USA.
² Environmental Influences on Health and Disease Group, Sanford Research, Sioux Falls, SD 57104, USA.
³ Department of Exercise and Nutrition Sciences, State University of New York, Buffalo, NY 14214, USA.
⁴ Boekelheide Neonatal Intensive Care Unit, Sanford Children's Hospital, Sioux Falls, SD 57117, USA.

Abstract

Infants of diabetic mothers are at risk of cardiomyopathy at birth and myocardial infarction in adulthood, but prevention is hindered because mechanisms remain unknown. We previously showed that maternal glucolipotoxicity increases the risk of cardiomyopathy and mortality in newborn rats through fuel-mediated mitochondrial dysfunction. Here we demonstrate ongoing cardiometabolic consequences by cross-fostering and following echocardiography, cardiomyocyte bioenergetics, mitochondria-mediated turnover, and cell death following metabolic stress in aged adults. Like humans, cardiac function improves by weaning with no apparent differences in early adulthood but declines again in aged diabetes-exposed offspring. This is preceded by impaired oxidative phosphorylation, exaggerated age-related increase in mitochondrial number, and higher oxygen consumption. Prenatally exposed male cardiomyocytes have more mitolysosomes indicating high baseline turnover; when exposed to metabolic stress, mitophagy cannot increase and cardiomyocytes have faster mitochondrial membrane potential loss and mitochondria-mediated cell death. Details highlight age- and sex-specific roles of mitochondria in developmentally programmed adult heart disease.

Keywords: Animal Physiology; Biological Sciences; Cell Biology; Diabetology; Molecular Biology; Physiology.

Abstract

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