Abstract

Mitochondrial function requires the coordinate synthesis of proteins encoded in the nucleus and the organellar genome. The long-term goal of this research is to understand how mitochondrial gene expression is regulated. The focus is on the subset of yeast nuclear genes encoding proteins that enter the organelle to participate in post-transcriptional processes. Each of the seven mitochondrial mRNAs require several message-specific factors that regulate intron removal, mRNA stability and translation. Cbpl has been studied in-depth. It is required specifically for cytochrome b mRNA stability. Recently Cbpl was found to be part of a large multisubunit complex. Cbs2, a factor that specifically promotes translation of COB, is also in a large complex of similar mass.
Specific Aim 1 is to analyze the composition and function of these large complexes in RNA protection and translation.
Specific Aim 2 is to determine if the two functions of Cbpl, message stabilization and translation, are separable.
Specific Aim 3 is to characterize Aep3 in its roles in protection and translation of ATP8/6 mRNA. In addition to the studies on message-specific factors that protect mRNAs and promote their translation, several general factors are important in the turnover of the mRNAs. Overexpression of the Cbt1 protein suppresses mRNA instability, whereas deletion of the CBT1 gene results in defective processing of precursor RNAs. Three other mitochondrial proteins have been implicated in these processing events and mRNA turnover. Cbt1 is in a large complex of proteins of 500,000 daltons.
Specific Aim 4 is to analyze the composition and function of this large complex in precursor RNA processing and mRNA turnover. This work will further our general understanding of RNA expression in mitochondria. Many human diseases are caused by mutations in nuclear genes that regulate mitochondrial gene expression. Yeast is a good model system to understand processes that may be affected in human mitochondrial disease syndromes.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM034893-19
Application #
7093030
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Poodry, Clifton A
Project Start
1985-04-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
19
Fiscal Year
2006
Total Cost
$294,903
Indirect Cost

  Institution

Name
University of Arizona
Department
Biochemistry
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721

  Publications

Hiltunen, J Kalervo; Autio, Kaija J; Schonauer, Melissa S et al. (2010) Mitochondrial fatty acid synthesis and respiration. Biochim Biophys Acta 1797:1195-202
Hiltunen, J Kalervo; Schonauer, Melissa S; Autio, Kaija J et al. (2009) Mitochondrial fatty acid synthesis type II: more than just fatty acids. J Biol Chem 284:9011-5
Schonauer, Melissa S; Kastaniotis, Alexander J; Kursu, V A Samuli et al. (2009) Lipoic acid synthesis and attachment in yeast mitochondria. J Biol Chem 284:23234-42
Fekete, Zsuzsanna; Ellis, Timothy P; Schonauer, Melissa S et al. (2008) Pet127 governs a 5'->3'-exonuclease important in maturation of apocytochrome b mRNA in Saccharomyces cerevisiae. J Biol Chem 283:3767-72
Schonauer, Melissa S; Kastaniotis, Alexander J; Hiltunen, J Kalervo et al. (2008) Intersection of RNA processing and the type II fatty acid synthesis pathway in yeast mitochondria. Mol Cell Biol 28:6646-57
Ellis, Timothy P; Schonauer, Melissa S; Dieckmann, Carol L (2005) CBT1 interacts genetically with CBP1 and the mitochondrially encoded cytochrome b gene and is required to stabilize the mature cytochrome b mRNA of Saccharomyces cerevisiae. Genetics 171:949-57
Ellis, Timothy P; Helfenbein, Kevin G; Tzagoloff, Alexander et al. (2004) Aep3p stabilizes the mitochondrial bicistronic mRNA encoding subunits 6 and 8 of the H+-translocating ATP synthase of Saccharomyces cerevisiae. J Biol Chem 279:15728-33
Krause, Kirsten; Dieckmann, Carol L (2004) Analysis of transcription asymmetries along the tRNAE-COB operon: evidence for transcription attenuation and rapid RNA degradation between coding sequences. Nucleic Acids Res 32:6276-83
Krause, Kirsten; Lopes de Souza, Renata; Roberts, Douglas G W et al. (2004) The mitochondrial message-specific mRNA protectors Cbp1 and Pet309 are associated in a high-molecular weight complex. Mol Biol Cell 15:2674-83
Islas-Osuna, Maria A; Ellis, Timothy P; Mittelmeier, Telsa M et al. (2003) Suppressor mutations define two regions in the Cbp1 protein important for mitochondrial cytochrome b mRNA stability in Saccharomyces cerevisiae. Curr Genet 43:327-36

Showing the most recent 10 out of 29 publications