Mitochondria are unusual among the organelles of a eukaryotic cell in that they possess their own genome, the mtDNA. The replication and transcription of mtDNA and the translation of the mtDNA- encoded proteins is essential for the production of ATP by oxidative phosphorylation. Evolutionary analyses and molecular studies of human mtDNA indicate that recombination of human mtDNA occurs. Recombination of mtDNA occurs at low levels in healthy individuals and results in the accumulation of mtDNA rearrangements, whose levels increase with age. At high levels, mtDNA rearrangements can result in mitochondrial dysfunction and human disease. It is difficult to observe mtDNA recombination experimentally in cells because of the lack of appropriate mtDNA markers to detect recombination. A model system is described here that uses uniquely marked human mtDNAs that permit the detection of inter-molecular and intra-molecular recombinant mtDNAs. This system of analysis will be used to identify the products of mtDNA recombination and to determine their rates of formation. Subsequently, the mechanisms by which recombinant mtDNAs are formed in cells will be investigated. These investigations are likely to lead to significant,insights into the mechanism for formation of pathogenic mtDNA rearrangements, as well as into fundamental cellular processes involving mtDNA including mtDNA maintenance, replication, and repair mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM071750-03
Application #
7342385
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Anderson, Richard A
Project Start
2006-02-01
Project End
2010-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
3
Fiscal Year
2008
Total Cost
$260,751
Indirect Cost
Name
Thomas Jefferson University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107