Chronic ethanol (EtOH) exposure and AIDS exposure are known to cause cardiomyopathy, and to act synergistically when combined. Moreover, both ethanol and AIDS exposure have been observed to inhibit mitochondrial function, alter mitochondrial structure, and increase oxidative stress. Inhibition of mitochondrial oxidative phosphorylation reduces mitochondrial energy production and increases mitochondrial reactive oxygen species (ROS) generation, which have been linked to hypertrophic cardiomyopathy and dilated cardiomyopathy, respectively. Therefore, we hypothesize that both ethanol and AIDS exposure induce cardiomyopathy by reducing mitochondrial energy production through the direct disruption of OXPHOS and the indirect inhibition of OXPHOS by mitochondrial ROS. To test this hypothesis, we propose to challenge mice harboring various genetic defects in mitochondrial energy production and ROS detoxification to chronic ethanol, murine AIDS (MAIDS), and ethanol plus MAIDS exposure. The four strains will include (1) wildtype mice, (2) mice deficient (-/-) in the mitochondrial heart-muscle isoform of the adenine nucleotide translocator (ANT1), (3) mice partially deficient (+/-) in the mitochondrial Mn superoxide dismutase (MnSOD), and (4) mice deficient (-/-)in the glutathione peroxidase (GPx). The ANTI-defect reduces mitochondrial ATP availability to the heart and predisposes to hypertrophic cardiomyopathy. The MnSOD-defect increases mitochondrial ROS production and leads to dilated cardiomyopathy. The GPx1 -defect increases cardiac cytosolic hydrogen peroxide levels and increases the potential for viral myocarditis. Control, ethanol, MAIDS, and ethanol + MAIDS exposed mice will then be analyzed for cardiac pathology, changes in cardiac mitochondrial OXPHOS, increased cardiac oxidative damage, and alterations in the expression of mitochondrial and oxidative stress gene expression. If the ANT -/- animals develop a more severe hypertrophic cardiomyopathy and an increased predilection to dilated cardiomyopathy an ethanol and MAIDS exposure then this will indicate that mitochondrial energy deficiency is important in cardiomyopathy. If the MnSOD +/- animals have an increased frequency of dilated cardiomyopathy, then this will implicate mitochondrial ROS toxicity. If the GPx1 -/- animals have an increased incidence of myocarditis, then this will indicate that cytosolic oxidative stress is important in induced cardiomyopathy.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Special Emphasis Panel (ZHL1-CSR-K (M2))
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Gerschenson, Mariana
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University of California Irvine
Schools of Arts and Sciences
United States
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Lee, Jaewon; Schriner, Samuel E; Wallace, Douglas C (2009) Adenine nucleotide translocator 1 deficiency increases resistance of mouse brain and neurons to excitotoxic insults. Biochim Biophys Acta 1787:364-70
Wallace, Douglas C (2007) Why do we still have a maternally inherited mitochondrial DNA? Insights from evolutionary medicine. Annu Rev Biochem 76:781-821
Ruiz-Pesini, Eduardo; Lott, Marie T; Procaccio, Vincent et al. (2007) An enhanced MITOMAP with a global mtDNA mutational phylogeny. Nucleic Acids Res 35:D823-8
Procaccio, Vincent; Neckelmann, Nicolas; Paquis-Flucklinger, Veronique et al. (2006) Detection of low levels of the mitochondrial tRNALeu(UUR) 3243A>G mutation in blood derived from patients with diabetes. Mol Diagn Ther 10:381-9
Ruiz-Pesini, Eduardo; Wallace, Douglas C (2006) Evidence for adaptive selection acting on the tRNA and rRNA genes of human mitochondrial DNA. Hum Mutat 27:1072-81
Brandon, M; Baldi, P; Wallace, D C (2006) Mitochondrial mutations in cancer. Oncogene 25:4647-62
Wallace, Douglas C (2005) A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39:359-407
Brandon, Marty C; Lott, Marie T; Nguyen, Kevin Cuong et al. (2005) MITOMAP: a human mitochondrial genome database--2004 update. Nucleic Acids Res 33:D611-3
Wallace, D C (2005) Mitochondria and cancer: Warburg addressed. Cold Spring Harb Symp Quant Biol 70:363-74
Flierl, A; Chen, Y; Coskun, P E et al. (2005) Adeno-associated virus-mediated gene transfer of the heart/muscle adenine nucleotide translocator (ANT) in mouse. Gene Ther 12:570-8

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