Mitochondria are commonly referred to as the "power house" of the cell where the majority of cellular energy is produced. These are unique organelles in that they house their own mitochondrial genome (mtDNA) as well as their own DNA replication, transcription and translation enzymes. The human mitochondrial genome encodes for 13 integral subunits of the oxidative phosphorylation (OXPHOS) pathway. Approximately 80 protein subunits are necessary to generate the enzymatic complexes of this pathway, and the remaining protein subunits are encoded by the nucleus, translated in the cytosol and then imported into the mitochondrial inner membrane. For this to be an efficient process coordination must take place between nuclear and mitochondrial gene expression, and this proposal addresses the role of thyroid hormone and its receptor (thyroid hormone receptor 1, specifically THR11) as a mechanism for this coordination in human cells. The traditional role for hormone receptors has been primarily as nuclear receptors that act as ligand-activated transcription factors. In fact some OXPHOS genes in the nucleus have hormone response elements in their promoter regions, as well as other nuclear genes that encode mtDNA regulatory factors. A new role for THR11 was revealed after it was determined that a variant form also localizes to mitochondria (mt-THR11). It is well established that mitochondrial mRNA synthesis and mitochondrial biogenesis is stimulated by thyroid hormone, and we hypothesize this is a direct result of mt-THR11 binding to thyroid response elements (TREs) in the mtDNA and acting as a mitochondrial transcription factor.
The specific aims of this research proposal will use in vitro and in vivo experiments to determine if mt-THR11 can directly promote mitochondrial transcription, and how mt-THR11 interacts with the mtDNA and the core human mitochondrial transcription machinery. Finally, the mechanism of mitochondrial mRNA up-regulation will be further addressed by determining the effect of mt-THR11 on mtDNA promoter utilization in response to thyroid hormone exposure and treatment. Determining this mechanism of action will give significant insight into the coordination of gene expression between the nucleus and mitochondrial genomes in human cells in response to a physiological signal. This research proposal aims to provide further understanding for the role of mitochondria in human disease and metabolic disorders such as diabetes.

Public Health Relevance

Metabolic diseases affect a large number of people throughout the population including those with diabetes and other hormone related disorders such as thyroid hormone resistance and estrogen/testosterone problems. This research proposal is relevant to this aspect of public health as it directly assess the role of thyroid hormone and its cellular receptor in energy metabolism and mitochondrial function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DK091042-02
Application #
8265826
Study Section
Special Emphasis Panel (ZDK1-GRB-W (O1))
Program Officer
Castle, Arthur
Project Start
2011-07-01
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$52,190
Indirect Cost
Name
Yale University
Department
Pathology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Lodeiro, Maria F; Uchida, Akira; Bestwick, Megan et al. (2012) Transcription from the second heavy-strand promoter of human mtDNA is repressed by transcription factor A in vitro. Proc Natl Acad Sci U S A 109:6513-8
Malarkey, Christopher S; Bestwick, Megan; Kuhlwilm, Jane E et al. (2012) Transcriptional activation by mitochondrial transcription factor A involves preferential distortion of promoter DNA. Nucleic Acids Res 40:614-24