Mitochondria are the main sources of energy in the cell. They are unique mammalian organelles because they contain their own DNA (mtDNA), whose genes encode components of the respiratory chain/oxidative phosphorylation system. They are essential for the normal functioning of all cells in the body, and are absolutely for the function of those tissues that are highly dependent on aerobic metabolism, including heart and skeletal muscle and brain. Since 1988, over 50 mtDNA point mutations have been reported. Of the 13 mtDNA point mutations in patients with clinically exclusive or predominant cardiomyopathy, six were identified by group. The applicant proposes to continue his studies of human cardiomyopathies along three lines of investigations. First he will screen patients for known and novel mtDNA mutations, focusing on patients with cardiomyopathies are maternally-inherited, sporadic hypertrophic, or associated with neurological features. Second, he will determine the molecular genetic defect in the Autosomal Recessive Cardiomyopathy Ophthalmoplegia (ARCO) syndrome associated with multiple mtDNA deletions. Understanding this disorder will likely promote our knowledge of the intergenomic communication between the nucleus and mitochondria. Third, he will study the effects to two different pathogenic mtDNAs that cause cardiomyopathy using the powerful cybrid tissue culture system which allows him to fuse cytoplasts containing a mtDNA mutation with rho cells which are devoid of mtDNA. Thus, he can study the in vitro consequences of a mtDNA mutation against a uniform nuclear DNA background. If attempts to an immortalized human cardiomyocyte cell line are successful, he will create cardiomyocyte cybrids to test tissue-specific effects of the mtDNA mutations. Through his proposed studies, he hopes to better understand the spectrum and the pathogenesis of mtDNA mutations in human cardiomyopathies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059657-04
Application #
6183958
Study Section
Special Emphasis Panel (ZHL1-CSR-N (S1))
Project Start
1997-09-30
Project End
2002-08-31
Budget Start
2000-09-01
Budget End
2002-08-31
Support Year
4
Fiscal Year
2000
Total Cost
$255,750
Indirect Cost
Name
Columbia University (N.Y.)
Department
Neurology
Type
Schools of Medicine
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
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Nishigaki, Yutaka; Tadesse, Saba; Bonilla, Eduardo et al. (2003) A novel mitochondrial tRNA(Leu(UUR)) mutation in a patient with features of MERRF and Kearns-Sayre syndrome. Neuromuscul Disord 13:334-40
Nishigaki, Y; Bonilla, E; Shanske, S et al. (2002) Exercise-induced muscle ""burning,"" fatigue, and hyper-CKemia: mtDNA T10010C mutation in tRNA(Gly). Neurology 58:1282-5
Giordano, Carla; Pallotti, Francesco; Walker, Winsome F et al. (2002) Pathogenesis of the deafness-associated A1555G mitochondrial DNA mutation. Biochem Biophys Res Commun 293:521-9
Hirano, Michio; DiMauro, Salvatore (2002) Metabolic myopathies. Adv Neurol 88:217-34
Hirano, M; Davidson, M; DiMauro, S (2001) Mitochondria and the heart. Curr Opin Cardiol 16:201-10
Hirano, M; Marti, R; Ferreiro-Barros, C et al. (2001) Defects of intergenomic communication: autosomal disorders that cause multiple deletions and depletion of mitochondrial DNA. Semin Cell Dev Biol 12:417-27
Hirano, M; Vu, T H (2000) Defects of intergenomic communication: where do we stand? Brain Pathol 10:451-61
Nishino, I; Spinazzola, A; Hirano, M (1999) Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 283:689-92
DiMauro, S; Hirano, M (1998) Mitochondria and heart disease. Curr Opin Cardiol 13:190-7

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