Cardiovascular disease is the leading cause of death among people with diabetes and may occur in the absence of other known risk factors. Mitochondrial bioenergetic deficits and increased free radical production are pathological hallmarks of diabetic cardiomyopathy (DCM). A goal of this project is to determine the molecular changes that occur in mitochondria to induce metabolic dysfunction and oxidative stress. Specifically, we are addressing how dysregulated mitochondrial protein lysine acetylation contributes to metabolic inflexibility, mitochondrial dysfunction, and the progression of DCM. Our hypothesis is that hyperglycemia leads to increased, pathological protein lysine acetylation of specific metabolic enzymes, such as protein kinase A, and this contributes to fatty acid oxidation, mitochondrial dysfunction, and increased oxidative stress. Using a transgenic rodent model of type 1 diabetes and cell culture techniques, we will test the hypothesis as follows:
Aim 1. Define the changes that occur to mitochondria that lead to mitochondrial dysfunction and increased oxidative stress with the progression of diabetes. Mitochondrial substrate selection, oxidative phosphorylation, and free radical production will be analyzed in parallel with changes in cardiac structure and function using magnetic resonance imaging (MRI) and histology.
Aim 2. Define the contribution of hyper-acetylation to mitochondrial dysfunction. The consequences of hyper-acetylation on oxidative phosphorylation, oxidative stress, and diabetic cardiomyopathy will be determined. This will be done by a) MS analysis of acetylated proteins;b) identifying the functional changes that hyperacetylation induces;and c) identifying the cause of diabetes induced hyperacetylation.
Aim 3. Determine the role of PKA in contributing to metabolic inflexibility and mitochondrial dysfunction.
This aim will test the hypothesis that our observed decrease in PKA activity is mediated by oxidation and/or acetylation. Mechanistic studies will determine the occurrence and consequences of these modifications on mitochondrial respiratory activity and free radical production.
Heart disease is a leading cause of disability and death in people with diabetes. The goal of this project is to understand how changes in metabolism induced by diabetes leads to increases in free radical production, bioenergetic deficits, and cardiac disease.
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