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Mitochondrial gene expression and human disease

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  • Full or part time
    Dr M Minczuk
  • Application Deadline
    Applications accepted all year round

Project Description

Post-transcriptional control of RNA stability, processing, modification, and degradation is key to the regulation of gene expression in all living cells. In mitochondria, these post-transcriptional processes are also vital for proper expression of the thirteen proteins encoded by the mitochondrial genome, as well as mitochondrial tRNAs and rRNAs. Our knowledge on mitochondrial RNA (mt-RNA) metabolic pathways, however, is far from complete. All of the proteins involved in mt-RNA metabolism are encoded by the nucleus, and must be imported into the organelle. Mutations in these nuclear genes can lead to perturbations in mitochondrial RNA processing, modification, stability and decay and thus are a cause of human mitochondrial disease. The aim of the project is to study nuclear genes involved in mt-RNA metabolism in order to understand how their dysfunction is linked with human mitochondrial pathologies. Next generation RNA sequencing technology will be the main tool for characterising mitochondrial RNA abundance, processing and maturation events in the context of pathological mutation, up- or down regulation of specific RNA-transacting factors, therefore, strong background in bioinformatics is required from the candidates.

General keywords: molecular biology, genetics, human disease, mitochondrial medicine
More specific keywords: mitochondrial diseases, mitochondrial gene expression

Funding Notes

For entry in 2016/17: Applications from self-funded or sponsored students will be considered.


Our recent experimental papers:
1. Kopajtich, R., Nicholls, T.J., Rorbach, J., Metodiev, M.D. et al. (2014) Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis and encephalopathy Am J Hum Genet – in press
2. Rorbach, J., Boesch, P., Gammage, P.A., Nicholls, T.J., Pearce, S.F., Patel, D., Hauser, A., Perocchi, F., Minczuk, M. (2014) MRM2 and MRM3 are involved in biogenesis of the large subunit of mitochondrial ribosome. Mol Biol Cell 25, 2542-2555
3. Haack, T.B. et al. (2013) ELAC2 Mutations Cause a Mitochondrial RNA Processing Defect Associated with Hypertrophic Cardiomyopathy. Am J Hum Genet 93, 211–223
4. Kornblum, C. Nicholls, T.J, Haack, T.B. et al., (2013) Loss-of-function mutations in MGME1 impair mtDNA replication and cause multi-systemic mitochondrial disease. Nat. Genet 45, 214-9
5. Rorbach, J., Gammage, P.A., Minczuk, M. (2012) C7orf30 is necessary for biogenesis of the large subunit of the mitochondrial ribosome. Nucleic Acids Res 40, 4097-4109
6. Rorbach, J., Nicholls, T.J., Minczuk, M. (2011) PDE12 removes mitochondrial RNA poly(A) tails and controls translation in human mitochondria. Nucleic Acids Res 39, 7750-63.

Our recent reviews
1. Nicholls, T.J., Rorbach, J., Minczuk, M. (2013) Mitochondrial RNA metabolism and human disease Int J Biochem Cell Biol 45, 845-9
2. Rorbach, J. & Minczuk M. (2012) The post-transcriptional life of mammalian mitochondrial RNA Biochem J. 444, 357-373

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