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

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 diabetesexposed 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.

Mitochondrial Transfer Improves Cardiomyocyte Bioenergetics and Viability in Male Rats Exposed to Pregestational Diabetes

“…Stroke volume was 14% lower in HF diet-exposed offspring leading to significantly lower cardiac output ( Figure 1 C,D). As with LGDM [ 9 , 10 ], combination-exposed offspring had the poorest systolic and diastolic function and cardiac output. Pulmonary hypertension was not found in PGDM- or HF diet-exposed offspring ( Table S1 ).…”

“…Diabetes and obesity during pregnancy expose the fetus to excess circulating glucose and lipids, inciting fetal hyperinsulinemia and fuel-mediated heart disease at birth [ 1 , 2 , 3 , 4 ] and later in life [ 5 , 6 , 7 ], yet prevention is hindered because mechanisms are not well understood. Work from our lab [ 8 , 9 , 10 , 11 , 12 ] and others [ 13 , 14 , 15 ] suggests that mitochondria play a central, pathogenic role, specifically in offspring exposed to late-gestation diabetes mellitus (LGDM) and maternal high-fat (HF) diet. This study aimed to answer key remaining questions.…”

“…Using a rat model of LGDM and HF diet that prenatally exposes offspring to maternal hyperglycemia, hyperlipidemia, and fetal hyperinsulinemia in the last third of pregnancy, we found that newborn rats exposed to diabetic pregnancy have larger hearts with diastolic and systolic dysfunction [ 9 , 10 ] similar to humans [ 2 ]. Their isolated cardiomyocytes (CM) have intrinsic mitochondrial dysfunction with impaired dynamics, bioenergetics, and sex-specific differences in mitochondrial complex function that is worsened in combination with maternal HF diet [ 8 , 9 , 10 ]. As adults, LGDM-exposed male offspring have faster mitochondrial membrane potential (MMP) loss and mitochondria-mediated death under stress [ 9 ].…”

“…Their isolated cardiomyocytes (CM) have intrinsic mitochondrial dysfunction with impaired dynamics, bioenergetics, and sex-specific differences in mitochondrial complex function that is worsened in combination with maternal HF diet [ 8 , 9 , 10 ]. As adults, LGDM-exposed male offspring have faster mitochondrial membrane potential (MMP) loss and mitochondria-mediated death under stress [ 9 ]. Others have described lasting cardiovascular consequences resulting from metabolic memory, the concept that exposure to even transient hyperglycemia imparts lasting effects through epigenetic modification and oxidative stress [ 17 , 18 ].…”

“…To mechanistically isolate and test the role of mitochondria in CM bioenergetic dysfunction and cell fate, we combined mitochondrial transfer (often termed “mitochondrial transplantation” in in vivo models) with Seahorse extracellular flux analyses, confocal imaging for mitophagy, and our carbonyl cyanide-4-phenylhydrazone (FCCP) Challenge, which quantifies MMP loss and cell death responses to respiratory stress, much like a “heart attack in a dish” [ 9 ]. Mounting in vitro and in vivo studies have shown that isolated mitochondria with intact respiration can be injected or perfused into the heart, where they are quickly internalized by CM [ 19 , 20 , 21 ] via actin-dependent endocytosis [ 22 ].…”