Since our initial demonstration that mitochondrial DNA (mtDNA) mutations can result in Type II diabetes, considerable evidence has accumulated supporting the hypothesis that Type II diabetes is the product of inherited partial mitochondrial oxidative phosphorylation (OXPHOS) deficiency which inhibitsthe mitochondrial metabolism of calories and increases mitochondrial production of reactive oxygen species (ROS). The oxidative stress form the ROS further erodes mitochondrial function in both target tissues and in pancreatic p cells, leading to insulin resistance, loss of insulin secretion, and (3 cells apoptosis. To further clarify the role of mtDNA mutations in Type II diabetes, we propose to identify the inherited mtDNA mutations causing diabetes in a number of maternally inherited diabetes pedigrees. We will then use the cybrid transfer technique to place these mutations onto hepatic and pancreatic cell nuclear backgrounds and then the characterize these cybrid cell lines for the biochemical defects assoiated with the mtDNA mutations. These same cell lines with then be treated with metallopophyrin superoxide dismutase (SOD) mimetics to determine with these catalytic antioxidants can reduce ameliorate the biochemical defect caused by the mtDNA mutation. In addition, we will study mice with inherited defects in mitochondrial antioxidant defenses (Sod2) and in OXPHOS ATP production (Antl &Ant2) to correlate the development of diabetes with the age-related decline in mitochondrial function and the accumulation of somatic mtDNA mutations in both insulin target and insulin secreting tissues. These mice will also be treated with the metalloporphyrinmimetics to determine if these drugs will then delay the development of the symptoms and the accumulation of the somatic mtDNA mutations.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Special Emphasis Panel (ZDK1-GRB-N (O1))
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Jones, Teresa L Z
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University of California Irvine
Schools of Arts and Sciences
United States
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Morrow, Ryan M; Picard, Martin; Derbeneva, Olga et al. (2017) Mitochondrial energy deficiency leads to hyperproliferation of skeletal muscle mitochondria and enhanced insulin sensitivity. Proc Natl Acad Sci U S A 114:2705-2710
Kandel, Judith; Picard, Martin; Wallace, Douglas C et al. (2017) Mitochondrial DNA 3243A>G heteroplasmy is associated with changes in cytoskeletal protein expression and cell mechanics. J R Soc Interface 14:
Picard, Martin; Wallace, Douglas C; Burelle, Yan (2016) The rise of mitochondria in medicine. Mitochondrion 30:105-16
Potluri, Prasanth; Procaccio, Vincent; Scheffler, Immo E et al. (2016) High throughput gene complementation screening permits identification of a mammalian mitochondrial protein synthesis (?(-)) mutant. Biochim Biophys Acta 1857:1336-1343
Lin, Ran; Rittenhouse, Danielle; Sweeney, Katelyn et al. (2015) TSPO, a Mitochondrial Outer Membrane Protein, Controls Ethanol-Related Behaviors in Drosophila. PLoS Genet 11:e1005366
Picard, Martin; McManus, Meagan J; Gray, Jason D et al. (2015) Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress. Proc Natl Acad Sci U S A 112:E6614-23
Picard, Martin; McManus, Meagan J; Csordás, György et al. (2015) Trans-mitochondrial coordination of cristae at regulated membrane junctions. Nat Commun 6:6259
Picard, Martin; Zhang, Jiangwen; Hancock, Saege et al. (2014) Progressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming. Proc Natl Acad Sci U S A 111:E4033-42
Lin, Ran; Angelin, Alessia; Da Settimo, Federico et al. (2014) Genetic analysis of dTSPO, an outer mitochondrial membrane protein, reveals its functions in apoptosis, longevity, and Ab42-induced neurodegeneration. Aging Cell 13:507-18
Yang, Jia-Ying; Deng, Wu; Chen, Yumay et al. (2013) Impaired translocation and activation of mitochondrial Akt1 mitigated mitochondrial oxidative phosphorylation Complex V activity in diabetic myocardium. J Mol Cell Cardiol 59:167-75

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