Joanna Rorbach Group

Mitochondrial dysfunction is a major contributor to metabolic and neurodegenerative pathologies, ageing and cancer. Indeed, several key factors regulating mitochondrial gene expression are associated with a range of human diseases. The objective of our research is to better understand the post-transcriptional regulatory networks controlling gene expression in mitochondria; as a means to identify pathways and factors impinging upon physiology and disease.

Assistant professor

Joanna Rorbach

Phone: +46-(0)8-524 866 93
Organizational unit: Joanna Rorbach group
E-mail: joanna.rorbach@ki.se

Research Interest

Mammalian mitochondrial ribosomes synthesise a small subset of proteins that are important components of the oxidative phosphorylation machinery, therefore their function is of fundamental importance to cellular metabolism, viability and function.

Most studies of ribosome assembly and function have been carried out on bacterial and eukaryotic cytosolic ribosomes, which differ substantially from mammalian mitoribosomes both compositionally and mechanistically. At present, very little is known about the assembly pathways of mitoribosomes and their regulation. Moreover, many fundamental questions concerning the mechanistic aspects of mitochondrial protein synthesis remain. For example, we do not understand how the nascent protein products of translational machinery are inserted into the inner membrane of mammalian mitochondria.

Our research is directed towards overcoming this knowledge gap, providing a detailed description of mitochondrial ribosome biogenesis, membrane interaction, and structural and biochemical characterisation of different stages of protein synthesis. We employ highly multidisciplinary approaches to address these questions, including ribosome profiling, high-throughput gene targeting, proteomic and cryo-EM methods.

This studies will help us to identify novel factors, some of which may be implicated in disease.  In longer term, a description of these processes will yield valuable insight into how the mitochondrial gene expression is regulated, how and why errors occur, and how this impinges upon cellular function and leads to disease.

Work opportunities

We offer master student, PhD and Postdoc positions to highly motivated and enthusiastic researchers. For details please contact: joanna.rorbach@ki.se

Recent publications

Rorbach J*, Gao F*, Powell C, D’Souza A, Lightowlers RN, Minczuk M, Chrzanowska- Lightowlers ZMA. The human mitochondrial ribosome can switch its structural RNA composition. Proc Natl Acad Sci (2016) Oct 11.

Gammage PA, Gaude E, Van Haute L, Rebelo-Guiomar P, Jackson CB, Rorbach J, et al. Near-complete elimination of mutant mtDNA by iterative or dynamic dose-controlled treatment with mtZFNs. Nucleic Acids Res (2016) Sep 19;44(16):7804-16.

Van Haute L, Dietmann S, Kremer L, Hussain S, Pearce S, Powell C, Rorbach J, et al.  Deficient methylation and formylation of mt-tRNAMet wobble cytosine in a patient carrying mutations in NSUN3. Nat Commun (2016) Jun 30;7:12039.

Karniely S, Weekes MP, Antrobus R, Rorbach J, et al. Human Cytomegalovirus Infection Upregulates the Mitochondrial Transcription and Translation Machineries. MBio (2016) 29;7.

Powell C, Kopajtich R, Rorbach J, Dallabona C, et al. Mutations in TRMT5 cause a defect in post-transcriptional modification of mitochondrial tRNA associated with multiple respiratory-chain deficiencies. Am J Hum Genet (2015) 97:319-28.

Kopajtich R*, Nicholls TJ*, Rorbach J*, Metodiev MD*, Freisinger P, Mandel H, et al. Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis and encephalopathy. Am J Hum Genet (2014) 95(6): 708-20.

*equal contribution

Rorbach J, Boesch P, Gammage PA, Nicholls TJ, et al.  MRM2 and MRM3 are involved in biogenesis of the large subunit of the mitochondrial ribosome. Mol Biol Cell (2014) 25(17): 2542-55.

Gammage PA, Rorbach J, Vincent AI, Rebar EJ, Minczuk M. Mitochondrially targeted ZFNs for selective degradation of pathogenic mitochondrial genomes bearing large-scale deletions or point mutations. EMBO Mol Med (2014) 6(4): 458-66.

Rorbach J, Pearce S, Minczuk M. Polyadenylation of mRNA in Prokaryotes and organelles. Methods Mol Biol (2014) 1125:211-27.

Dalla Rosa I, Durigon R, Pearce SF, Rorbach J, Hirst EM, et al. MPV17L2 is required for ribosome assembly in mitochondria. Nucleic Acids Res (2014) 42(13): 8500-15.

Haack T, Kopajtich R, Freisinger P, Wieland T, Rorbach J, Nicholls TJ, et al. ELAC2 Mutations Cause Hypertrophic Cardiomyopathy and Lactic Acidosis Associated with a Mitochondrial RNA Processing and Translation Defect. Am J Hum Genet (2013) 93(2): 211-23.

Kornblum C, Nicholls TJ, Haack TB, Schöler S, Peeva V, Danhauser K, et al. Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease. Nature Genetics (2013) 45(2): 214-9.

Rorbach J, Minczuk M. The post-transcriptional life of mammalian mitochondrial RNA. Biochem J (2013) 444(3): 357-73.