2002 — 2007 |
Min, Kyung-Tai |
Z01Activity Code Description: Undocumented code - click on the grant title for more information. |
Drosophila Model of Mental Retardation in Down Syndrome @ Neurological Disorders and Stroke
Recently, in an effort to understand the signaling pathways controlling nebula/DSCR1, we discovered that nebula interacts with the adenine nucleotide translocator (ANT), a mitochondrial protein, and affects mitochondrial function. [unreadable] ANT is involved in the exchange of ADP/ATP and is the most abundant protein in the inner mitochondrial membrane. During aerobic respiration, electrons are passed through complexes I-IV of the electron transport chain to generate a proton gradient across the mitochondrial inner membrane. The movement of protons back to the mitochondrial matrix through complex V (ATP synthase) provides the energy to condense ADP and Pi to make ATP. Matrix ATP is then exported to the cytosol by ANT to provide the energy necessary for normal cellular function. In exchange, ADP is transported from the cytosol back into the mitochondrial matrix by ANT to allow further generation of ATP. Thus, ANT regulates the adenine nucleotide concentrations in the cytoplasm and within mitochondria, and is vital in coupling ATP synthesis to cellular energy demand. In addition to its translocase activity, ANT is an important component of the mitochondrial permeability transition pore (MPTP) and participates in mitochondrial-mediated apoptosis.[unreadable] ANT exists in multiple isoforms in a number of species and shows tissue-specific gene expression. The ANT-1 isoform (ANT1) in humans and mice is expressed in skeletal muscle, heart, eye, and brain. In humans, ANT1 mutation is associated with autosomal dominant progressive external opthalmoplegia (adPEO), an adult-onset mitochondrial disorder characterized by reduced activities of the respiratory-chain enzymes and multiple deletions of the mitochondrial genome. To delineate the role of ANT1 in mitochondrial diseases, ANT1 knockout mice were generated by Gram et al26, and these mice have ragged red muscle fibers with marked proliferation of mitochondria, exercise intolerance, and respiratory defects. ANT1 knockout mice also showed increased production of toxic mitochondrial reactive oxygen species (ROS) and increased mtDNA rearrangement. These findings directly demonstrate that a deficit in ATP/ADP transport can dramatically affect mitochondrial activity and number of mitochondria, and generate oxidative damage.
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2008 — 2009 |
Min, Kyung-Tai |
P20Activity Code Description: To support planning for new programs, expansion or modification of existing resources, and feasibility studies to explore various approaches to the development of interdisciplinary programs that offer potential solutions to problems of special significance to the mission of the NIH. These exploratory studies may lead to specialized or comprehensive centers. |
Biguanide Anti-Diabetics as a Potential Diet Restriction @ University of Alaska Fairbanks
This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Specific Aim: Biguanide anti-diabetics as a potential diet restriction mimetics was suggested a while ago (Dilman, 1971;Dilman and Anisimov, 1980) and there are growing evidences that metformin, FDA approved anti-diabetic drug, can modulate life span (Dhahbi et al., 2005;Anisimove et al., 2005). We would like to determine the effects of metformin on life span in fruit flies, Drosophila melanogaster. In preliminary experiments to measure the effects of metformin on lifespan at standard food concentration (10% sugar yeast diet), we found that 5 or 10mM metformin significantly extended lifespan in the standard lab strain, Canton-S. Abstract: Metformin, FDA approved anti-diabetic drug, has long been suggested to have anti-aging effects and to extend lifespan. We showed that metformin can significantly extend lifespan in the fruit fly, Drosophila melanogaster. Median lifespan of flies fed on metformin was increased by up to 33%. Neither reproduction nor food intake was decreased in the flies fed on metformin. Interestingly, feeding rate was slightly increased after metformin treatment. Lifespan extension by metformin was associated with increased resistance to environmental stresses such as starvation and oxidative stress. Work is now proposed to use Drosophila to determine the doses at which metformin functions, and whether the effect of metformin on lifespan depends on nutritional status. In addition, the powerful genetic tools available for Drosophila will be used to determine if metformin's effects are dependent of AMPK signaling. Results from this work will serve as the basis for a larger-scale proposal, and should lead to a better understanding of the mechanisms by which diet restriction extends lifespan.
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