Doctor of Philosophy (PhD)
Molecular Genetics & Cell Biology
Paras K Mishra, PhD
Diabetes mellitus (DM) is characterized by hyperglycemia, hyperlipidemia, and hypoinsulemia, each of which disrupt intracellular mechanisms in the heart. DM is a chronic metabolic disease delineated into two categories: insulin deficient-type 1 DM and insulin resistant-type 2 DM. Although they differ in underlying genetic and physiological factors, both significantly increase the risk of heart failure. Impaired insulin signaling shifts energy dependency from glycolysis towards fatty acid β-oxidation in the DM heart. This DM-induced metabolic shift increases mitochondrial stress leading to mitochondrial dysfunction and cell death in the heart. The metabolically entwined ferroptosis is a novel form of myocardial cell death activated by the accumulation of lipids and reactive oxygen species due to disruptions in mitochondrial function and iron signaling. Despite being hallmarks of DM, the relationship between ferroptosis and metabolic derangement in the DM heart remains unknown. microRNAs (miRNAs) are tiny, endogenous, noncoding RNAs that use mRNA interference to regulate gene expression and maintain molecular signaling throughout the body. miRNA-133a is abundant in the heart and acts as a regulator of metabolism, cell death, and cardiac homeostasis. As miR-133a is downregulated in the diabetic heart, we hypothesized that DM-induced loss of miR-133a causes metabolic disruption leading to ferroptotic cell death in the heart. We also investigated the extent of metabolic derangement in the DM heart. Our results showed that decreased levels of miR-133a contributes to DM-induced cardiac remodeling and dysfunction. DM hearts also demonstrated disrupted glycolysis, fatty acid β-oxidation, and ketolysis. Overexpression of miR-133a attenuated metabolism and protected mitochondrial function, thereby inhibiting ferroptosis. We conclude that preventing loss of miR-133a could be a novel approach to mitigating pathogenesis in the DM heart.
Kambis, Tyler, "Determining the Role of miR-133a in the Diabetic Heart" (2022). Theses & Dissertations. 656.
Available for download on Sunday, April 28, 2024