Author ORCID Identifier

https://orcid.org/0000-0001-8741-2240

Document Type

Dissertation

Date of Award

5-2023

Degree Name

Doctor of Philosophy (PhD)

Department

Basic Biomedical Science

First Advisor

Michelle L. Baack

Abstract

Offspring of diabetic and obese mothers (ODOM) have greater risks of heart disease at birth and later in life. However, prevention is hindered because underlying mechanisms are poorly understood. Mounting studies in the Developmental Origins of Health and Disease field suggest that mitochondria play key roles in developmentally programmed heart disease similar to the roles they play in cardiomyopathy in adults with diabetes and obesity. However, whether mitochondria are responsible for the short[1]and long-term cardiac disease seen in ODOM remains unknown. Here, we sought to delineate the roles of mitochondria in the hearts of ODOM, determine whether mitochondria are playing central or secondary roles in previously found bioenergetic dysfunction, and tease apart the different mitochondrial mechanisms in pregestational vs late-gestation diabetes exposure. This body of works shows that mitochondrial and cardiac dysfunction are present at birth, soon normalize, but then reappear later in life. Importantly, mitochondrial dysfunction per impaired bioenergetics precedes the declining cardiac function in diabetes-exposed offspring, supporting a causative mitochondrial role. These same offspring, particularly males, suffer from greater mitochondria-mediated cell death under metabolic stress that may translate to faster, more robust tissue damage during ischemia-reperfusion, thus increasing the risk of death from myocardial infarction. We resumed study of newborns to understand mitochondria-mediated mechanisms of programmed heart disease, including heritable risk and effect on earlier cardiac development. To do this, we adapted our late-gestation diabetes model to study pregestational diabetes alongside maternal high-fat diet. Although there were similar and overlapping changes in cardiac structure and function, distinct mitochondrial impairments resulted from pregestational diabetes exposure. Rather than impaired bioenergetics contributing to cardiac dysfunction as in our late-gestation model, pregestational diabetes exposure impaired ATP production, increased oxidative damage, and reduced cardiomyocyte capacity for surviving metabolic stress. This could have profound effects on cardiogenesis and ageing. Mitochondrial transplantation was used to understand whether mitochondria play a primary role rather than programmed changes in fuel storage or flux. This technique provided male diabetes-exposed cells with both a respiratory boost and improved viability. Taken together, findings support a central, pathogenic, and potentially targetable role of mitochondria in developmentally programmed heart disease.

Subject Categories

Biochemistry | Cell Biology | Developmental Biology

Keywords

Cardiac function, Developmentally programmed heart disease, Diabetic pregnancy, High-fat diet, Metabolism, Mitochondria

Number of Pages

205

Publisher

University of South Dakota

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