Mitochondria have been shown to play a role in many human diseases. Specific mutations in the mitochondrial genome MARCH 9, 2001 MCCULLOCH, APRIL V. lead to a variety of multi-systemic disorders that affect the heart, nervous system and skeletal muscle. Mitochondrial dysfunction has also been implicated in Alzheimer?s disease, Parkinson?s disease, and in the control of apoptosis. Therefore, fully characterizing the requirements for proper mitochondrial gene expression in humans is critical, especially if one wants to understand how these processes can lead to specific disease states. The overall goal of this proposal is to characterize the proteins required for transcription initiation and transcription-coupled processes in human mitochondria, and there are three specific aims of the research project directed toward this goal.
The first aim i s to determine precisely which proteins make up the transcription complex in human mitochondria, as only two factors, h-mtTFA and h-mtRNA polymerase, are known to be required for mtDNA transcription. It has been found in the yeast Saccharomyces cerevisiae that an amino-terminal domain of mtRNA polymerase is required for maintenance of mtDNA and to couple R.NA processing events to transcription.
The second aim i s to determine if the amino-terminal extension of the human mtRNA polymerase forms a functional domain that couples other events to transcription. Finally, the candidate and the sponsor?s preliminary data suggest that h-mtRNA polymerase interacts with the mitochondrial ribosomal protein, MRPLI2. Because MRPL12 is encoded in the nucleus, this might be one means by which the nucleus could regulate gene expression in the mitochondria.
Specific aim three is to determine if this interaction is functionally significant and which processes are affected by this interaction in mitochondria.
| McCulloch, Vicki; Shadel, Gerald S (2003) Human mitochondrial transcription factor B1 interacts with the C-terminal activation region of h-mtTFA and stimulates transcription independently of its RNA methyltransferase activity. Mol Cell Biol 23:5816-24 |
| McCulloch, Vicki; Seidel-Rogol, Bonnie L; Shadel, Gerald S (2002) A human mitochondrial transcription factor is related to RNA adenine methyltransferases and binds S-adenosylmethionine. Mol Cell Biol 22:1116-25 |
