Mitochondrial dysfunction, mediated by changes in the production of ROS/RNS, plays an important role in the etiology of diabetes and offers a potential target for therapeutic intervention. Hyperglycemia results in progressive mitochondrial damage which can be assessed by changes in the mitochondrial proteome, cardiac dysfunction, and ultimately cell death. The underlying mechanisms leading to these changes have a major contribution from the post-translational modification of mitochondrial proteins and mitochondrial DMA. This proposal has the objective of developing mitochondrially targeted drugs that increase the degradation of intracellular ROS or RNS for the correction of the mitochondrial defects associated with hyperglycemia in cell and animal models of diabetes. It involves a consortium of investigators from the Medical College of Wisconsin and the University of Alabama at Birmingham and combines expertise in the measurement of ROS/RNS, the chemical synthesis of novel mitochondrially targeted antioxidants, mitochondrial proteomics and cell and animal models of diabetes. The consortium has the ability to design, characterize and optimize mitochondrial antioxidants in the large quantities necessary for assessment of efficacy in animal models of the disease. It is hypothesized that mitochondrially targeted antioxidants will ameliorate the ROS/RNS dependent modification of mitochondrial proteins, mtDNA damage and cardiac dysfunction that occurs in response to high glucose. This hypothesis will be examined using mitochondrial proteomics, cell biology and physiological approaches to model diabetes through pursuit of the following Specific Aims: 1: Synthesis and optimization of mitochondrially targeted antioxidants designed to decrease steady state levels of intra- mitochondrial superoxide, lipid radicals and peroxynitrite.
Specific Aim 2 : Screening of mitochondrially targeted antioxidants in cell culture systems.
Specific Aim 3 : Determine the impact of mitochondrially targeted antioxidants on mitochondrial dysfunction induced in an animal model of diabetes. The insights gained by the accomplishment of these specific aims will define the necessary elements for the successful design of mitochondrially targeted therapeutics. This would then act as the prelude to optimization of such compounds for clinical use in diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK075865-04
Application #
7784550
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Jones, Teresa L Z
Project Start
2007-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
4
Fiscal Year
2010
Total Cost
$383,581
Indirect Cost
Name
University of Alabama Birmingham
Department
Pathology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Pun, Pamela Boon Li; Logan, Angela; Darley-Usmar, Victor et al. (2014) A mitochondria-targeted mass spectrometry probe to detect glyoxals: implications for diabetes. Free Radic Biol Med 67:437-50
Mitchell, Tanecia; Johnson, Michelle S; Ouyang, Xiaosen et al. (2013) Dysfunctional mitochondrial bioenergetics and oxidative stress in Akita(+/Ins2)-derived ?-cells. Am J Physiol Endocrinol Metab 305:E585-99
Reily, Colin; Mitchell, Tanecia; Chacko, Balu K et al. (2013) Mitochondrially targeted compounds and their impact on cellular bioenergetics. Redox Biol 1:86-93
Dodson, Matthew; Darley-Usmar, Victor; Zhang, Jianhua (2013) Cellular metabolic and autophagic pathways: traffic control by redox signaling. Free Radic Biol Med 63:207-21
Cummins, Timothy D; Higdon, Ashlee N; Kramer, Philip A et al. (2013) Utilization of fluorescent probes for the quantification and identification of subcellular proteomes and biological processes regulated by lipid peroxidation products. Free Radic Biol Med 59:56-68
Higdon, Ashlee N; Benavides, Gloria A; Chacko, Balu K et al. (2012) Hemin causes mitochondrial dysfunction in endothelial cells through promoting lipid peroxidation: the protective role of autophagy. Am J Physiol Heart Circ Physiol 302:H1394-409
Mitchell, Tanecia; Chacko, Balu K; Darley-Usmar, Victor (2012) Controlling radicals in the powerhouse: development of MitoSOD. Chem Biol 19:1217-8
Hill, Bradford G; Benavides, Gloria A; Lancaster Jr, Jack R et al. (2012) Integration of cellular bioenergetics with mitochondrial quality control and autophagy. Biol Chem 393:1485-1512
Giordano, Samantha; Lee, Jisun; Darley-Usmar, Victor M et al. (2012) Distinct effects of rotenone, 1-methyl-4-phenylpyridinium and 6-hydroxydopamine on cellular bioenergetics and cell death. PLoS One 7:e44610
Mitchell, Tanecia; Darley-Usmar, Victor (2012) Metabolic syndrome and mitochondrial dysfunction: insights from preclinical studies with a mitochondrially targeted antioxidant. Free Radic Biol Med 52:838-40

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