Defects in oxidative phosphorylation (OXPHOS) have been associated with various neuromuscular degenerative processes. We propose to take advantage of current methodology that allows the manipulation of nuclear genes in embryonic stem cells and generate and characterize of mouse models with conditional mutations in nuclear-coded OXPHOS genes. The general hypotheses and questions this proposal will test are: i) What are the specific role of the knocked out factors on OXPHOS assembly and function? ii) Are different cell populations more susceptible to defects in specific OXPHOS complexes? iii) Do defects in specific respiratory chain complexes in muscle or nerves lead to different muscular or neurodegenerative phenotypes? iv) Are these phenotypes associated with different levels of oxidative damage or protein aggregation? Specifically, we will develop knock in mice for three respiratory complex genes in which an evolutionarily conserved exon is flanked by IoxP sites. The following genes will be manipulated: the NDUFS1 gene (complex I), Iron-Sulfur Protein (complex III) and COX10, a protoheme O farnesyl-transferase (required for heme a production and complex IV activity). The knockin animals will be crossed with mice expressing Cre-recombinase driven by CNS and skeletal muscle promoters. We expect these studies to provide evidence that specific defects in the OXPHOS can manifest as distinct phenotypic alterations. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041777-05
Application #
6994481
Study Section
Special Emphasis Panel (ZRG1-CDIN (01))
Program Officer
Porter, John D
Project Start
2001-06-01
Project End
2010-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
5
Fiscal Year
2006
Total Cost
$339,785
Indirect Cost
Name
University of Miami School of Medicine
Department
Neurology
Type
Schools of Medicine
DUNS #
052780918
City
Miami
State
FL
Country
United States
Zip Code
33146
Pickrell, Alicia M; Pinto, Milena; Moraes, Carlos T (2013) Mouse models of Parkinson's disease associated with mitochondrial dysfunction. Mol Cell Neurosci 55:87-94
Diaz, Francisca; Enriquez, Jose Antonio; Moraes, Carlos T (2012) Cells lacking Rieske iron-sulfur protein have a reactive oxygen species-associated decrease in respiratory complexes I and IV. Mol Cell Biol 32:415-29
Peralta, Susana; Wang, Xiao; Moraes, Carlos T (2012) Mitochondrial transcription: lessons from mouse models. Biochim Biophys Acta 1819:961-9
Diaz, Francisca; Garcia, Sofia; Padgett, Kyle R et al. (2012) A defect in the mitochondrial complex III, but not complex IV, triggers early ROS-dependent damage in defined brain regions. Hum Mol Genet 21:5066-77
Diaz, Francisca; Kotarsky, Heike; Fellman, Vineta et al. (2011) Mitochondrial disorders caused by mutations in respiratory chain assembly factors. Semin Fetal Neonatal Med 16:197-204
Rebelo, Adriana P; Dillon, Lloye M; Moraes, Carlos T (2011) Mitochondrial DNA transcription regulation and nucleoid organization. J Inherit Metab Dis 34:941-51
Diaz, Francisca (2010) Cytochrome c oxidase deficiency: patients and animal models. Biochim Biophys Acta 1802:100-10
Wenz, Tina; Williams, Sion L; Bacman, Sandra R et al. (2010) Emerging therapeutic approaches to mitochondrial diseases. Dev Disabil Res Rev 16:219-29
Bacman, S R; Williams, S L; Garcia, S et al. (2010) Organ-specific shifts in mtDNA heteroplasmy following systemic delivery of a mitochondria-targeted restriction endonuclease. Gene Ther 17:713-20
Williams, SiƓn L; Huang, Jia; Edwards, Yvonne J K et al. (2010) The mtDNA mutation spectrum of the progeroid Polg mutator mouse includes abundant control region multimers. Cell Metab 12:675-82

Showing the most recent 10 out of 37 publications