Defects in the mitochondrial respiratory complexes cause a number of metabolic diseases and are believed to play pivotal roles in the pathogenesis of age-related neurodegenerative disorders. Our laboratory's long term goal is to understand the biology of these conditions and develop effective treatments. To achieve these goals we have developed mouse models with defects in different mitochondrial respiratory complexes. We now propose to study the pathogenic mechanisms associated with defects in specific mitochondrial respiratory complexes (complexes I, III or IV). Our preliminary data showed some remarkable differences in the phenotypes depending on the complex affected. The identification of metabolic signatures of brains affected by the different defects will be used to better understand the pathogenic mechanisms. Finally, based on the information gathered in the first two aims, we will test whether increases in mitochondrial biogenesis and lipid utilization can have a protective effect for certain mitochondrial encephalopathies.

Public Health Relevance

Defects in mitochondrial respiratory complexes have been associated with many metabolic diseases. There is a great deal of variation in the clinical manifestations of these defects, but the reason for this is not known. We propose to study mouse models with defects in the respiratory complexes I, III and IV to better define the mechanisms responsible for the different clinical presentations. We will define metabolic signatures of deficient brains and use this information to fine tune therapeutic approaches based on an increase in mitochondrial biogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS079965-01
Application #
8359960
Study Section
Special Emphasis Panel (ZRG1-MDCN-F (03))
Program Officer
Gwinn, Katrina
Project Start
2012-05-15
Project End
2017-01-31
Budget Start
2012-05-15
Budget End
2013-01-31
Support Year
1
Fiscal Year
2012
Total Cost
$334,688
Indirect Cost
$115,938
Name
University of Miami School of Medicine
Department
Neurology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
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Peralta, Susana; Garcia, Sofia; Yin, Han Yang et al. (2016) Sustained AMPK activation improves muscle function in a mitochondrial myopathy mouse model by promoting muscle fiber regeneration. Hum Mol Genet 25:3178-3191
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Pinto, Milena; Nissanka, Nadee; Peralta, Susana et al. (2016) Pioglitazone ameliorates the phenotype of a novel Parkinson's disease mouse model by reducing neuroinflammation. Mol Neurodegener 11:25
Pinto, Milena; Moraes, Carlos T (2015) Mechanisms linking mtDNA damage and aging. Free Radic Biol Med 85:250-8
Arguello, Tania; Moraes, Carlos T (2015) Cre recombinase activity is inhibited in vivo but not ex vivo by a mutation in the asymmetric spacer region of the distal loxP site. Genesis 53:695-700
Hashimoto, Masami; Bacman, Sandra R; Peralta, Susana et al. (2015) MitoTALEN: A General Approach to Reduce Mutant mtDNA Loads and Restore Oxidative Phosphorylation Function in Mitochondrial Diseases. Mol Ther 23:1592-9
Pinto, Milena; Moraes, Carlos T (2014) Mitochondrial genome changes and neurodegenerative diseases. Biochim Biophys Acta 1842:1198-207
Bacman, Sandra R; Williams, Sion L; Pinto, Milena et al. (2014) The use of mitochondria-targeted endonucleases to manipulate mtDNA. Methods Enzymol 547:373-97
Moraes, Carlos T; Bacman, Sandra R; Williams, Sion L (2014) Manipulating mitochondrial genomes in the clinic: playing by different rules. Trends Cell Biol 24:209-11

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