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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM104934-08
Application #
8692935
Study Section
Special Emphasis Panel (ZRR1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Gao, Diansa; Zuo, Zhong; Tian, Jing et al. (2016) Activation of SIRT1 Attenuates Klotho Deficiency-Induced Arterial Stiffness and Hypertension by Enhancing AMP-Activated Protein Kinase Activity. Hypertension 68:1191-1199
Cheng, Rui; Ding, Lexi; He, Xuemin et al. (2016) Interaction of PPARα With the Canonic Wnt Pathway in the Regulation of Renal Fibrosis. Diabetes 65:3730-3743
Griffin, Timothy M; Humphries, Kenneth M; Kinter, Michael et al. (2016) Nutrient sensing and utilization: Getting to the heart of metabolic flexibility. Biochimie 124:74-83
Tsutsui, Yuko; Deredge, Daniel; Wintrode, Patrick L et al. (2016) Imatinib binding to human c-Src is coupled to inter-domain allostery and suggests a novel kinase inhibition strategy. Sci Rep 6:30832
He, Xuemin; Cheng, Rui; Park, Kyoungmin et al. (2016) Pigment epithelium-derived factor, a noninhibitory serine protease inhibitor, is renoprotective by inhibiting the Wnt pathway. Kidney Int :
Zhang, Zhi; Subramaniam, Sabareesh; Kale, Justin et al. (2016) BH3-in-groove dimerization initiates and helix 9 dimerization expands Bax pore assembly in membranes. EMBO J 35:208-36
Lin, Yi; Chen, Jianglei; Sun, Zhongjie (2016) Antiaging Gene Klotho Deficiency Promoted High-Fat Diet-Induced Arterial Stiffening via Inactivation of AMP-Activated Protein Kinase. Hypertension 67:564-73
Chen, Qian; Takahashi, Yusuke; Oka, Kazuhiro et al. (2016) Functional Differences of Very-Low-Density Lipoprotein Receptor Splice Variants in Regulating Wnt Signaling. Mol Cell Biol 36:2645-54
Varshney, Rohan; Ali, Quaisar; Wu, Chengxiang et al. (2016) Monocrotaline-Induced Pulmonary Hypertension Involves Downregulation of Antiaging Protein Klotho and eNOS Activity. Hypertension 68:1255-1263
(2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222

Showing the most recent 10 out of 60 publications