Date of Award
6-3-2025
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Molecular and Cellular Biochemistry Program
First Advisor
Qun Zang
Abstract
During sepsis, males often experience worse cardiac outcomes than females. Here, we identified pyruvate dehydrogenase kinase 4 (PDK4) as a key contributor to this disparity. PDK4 is a mitochondrial protein that regulates glucose utilization by inhibiting pyruvate dehydrogenase (PDH). Using a mouse model of endotoxemia, we induced acute inflammation with a sublethal dose of lipopolysaccharide (LPS), which caused cardiac dysfunction and significantly increased myocardial PDK4 expression in males but not females. Cardiac-specific PDK4 overexpression promoted LPS-induced cardiac dysfunction in both sexes, whereas cardiac-specific PDK4 knockout provided protection. In wild-type males, LPS disrupted cardiac metabolism by decreasing PDH activity and fatty acid oxidation (FAO) while increasing lactate levels, suggesting a shift from oxidative phosphorylation toward glycolysis. These responses were exacerbated by PDK4 overexpression but attenuated by PDK4 knockout. Conversely, in female hearts, LPS minimally affected these metabolic parameters, except for a reduction in FAO with transgenic PDK4 overexpression. Moreover, PDK4 overexpression exacerbated LPS-induced cardiac mitochondrial damage in both sexes, characterized by disrupted cristae, impaired membrane potential, increased fragmentation and reduced mitophagy. Mitochondrial damage was accompanied by increased oxidative stress and inflammation in the myocardium. PDK4 knockout prevented these detrimental effects. Collectively, these findings suggest that PDK4 drives sex-specific cardiac responses in sepsis.
Recommended Citation
Yap, John, "Pyruvate Dehydrogenase Kinase 4 Mediates Sex Specific Outcomes in Sepsis Induced Cardiomyopathy" (2025). Dissertations. 4184.
https://ecommons.luc.edu/luc_diss/4184
