Dataset Information

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

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 bioenergetics, and cardiac dysfunction at birth and again during aging. Here, we compared echocardiography, cardiomyocyte bioenergetics, oxidative damage, and mitochondria-mediated cell death among control, pregestational diabetes mellitus (PGDM)-exposed, HF-diet-exposed, and combination-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 peroxidation, 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.

SUBMITTER: Louwagie EJ

PROVIDER: S-EPMC7956857 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

Louwagie Eli J EJ Larsen Tricia D TD Wachal Angela L AL Gandy Tyler C T TCT Baack Michelle L ML

International journal of molecular sciences 20210227 5

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 bioenergetics, and cardiac dysfunction at birth and again during aging. Here, we compared echocardiography, cardiomyocyte bioenergetics, oxidative damage, and mitochondria-mediated cell death among control, pregestational diabe ...[more]

PMID: 33673574

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Project description:Mitochondria play a central role in energy homeostasis and act as regulatory checkpoints for downstream metabolic responses and cell senescence processes during an entire life span. Acute or chronic environmental toxicant exposures have shown deleterious organ-specific human health issues at various life stages. Since mitochondria are a prime target for ensuing cellular bioenergetics responses and senescence, it is essential to understand mitochondrial bioenergetic responses in different organs over multiple life stages. Therefore, in the present study, we evaluated mitochondrial bioenergetic parameters in the liver, lung, and heart in four diverse age groups (young: 1 month; adult: 4 months; middle-aged: 12 months; old-aged: 24 month) using male Brown Norway rats as a model of aging (n?=?5 sample size/organ/age group) and compared them with our previously published results on brain. Real-time mitochondrial bioenergetic parameters (i.e., State III, State IV, and State V) were measured using the Seahorse Extracellular Flux Analyzer. Additionally, mitochondrial enzyme pyruvate dehydrogenase complex (PDHC), Complex I, Complex II, and Complex IV activities were measured using Synergy HT plate reader. Our results indicated that nearly in all parameters, significant age- and organ-specific interactions were observed. We observed age-specific declines in State III (i.e., ATP synthesis rate) responses in both the heart and lung, where opposite was observed in the liver as age advances. Across the age, the heart has highest enzyme activities than the liver and lung. Interestingly, heart and liver mitochondrial bioenergetic rates and enzyme activities remain higher than the lung, which specifies their higher metabolic capabilities than the lung. Amongst all, bioenergetic rates and enzyme activities in the lung remain lowest suggesting the lung may display higher vulnerability and lower resilience to environmental toxicants during aging than other organs tested here. Overall, these age- and organ-specific findings may facilitate a more contextualized understanding of mitochondrial bioenergetic outcomes when considering the interactions of age-related sensitivities with exposure to chemical stressors from the environment.

Dataset Information

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

Publications

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

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