Mitochondrial Genetics: Mitochondrial genome engineering to unravel the genetic links between mitochondrial gene regulation and human disease for future mechanism-based therapies
Lead Research Organisation:
University of Cambridge
Department Name: UNLISTED
Abstract
In eukaryotic organisms almost all genetic information is encoded in DNA present in the nucleus of the cell, but a small DNA molecule inhabits mitochondria, cellular structures that provide energy from food for the cells to use. Mitochondrial DNA contains genes that are vital for the physiological functioning of the cell, and genetic defects causing dysfunction of mitochondrial DNA can lead to human diseases. We still do not know how mitochondrial genes work exactly. One of the ways to investigate the role of a gene, or to discover its biological function, it to change or disrupt DNA, and then to look for the effect on cultured cells, or on the whole organism. These methods of genetic modification are often powerful ways of studying disease genes encoded in the nucleus, but they are challenging to be applied to mammalian mitochondrial DNA. Also, many genes regulating mitochondrial function are still unknown. Therefore, our research goals are to identify new genes regulating mitochondria, define how these mitochondrial genes operate and to provide the technology to allow mammalian mitochondrial DNA to be modified genetically. It could be an invaluable way of understanding mitochondrial diseases and for advancing the quest for therapies.
Technical Summary
Mitochondrial diseases caused by mutations in mitochondrial DNA (mtDNA) or mutations in the nuclear genome (nDNA) impair energy metabolism and other aspects of cellular homeostasis. More than half of mitochondrial diseases stem from defects of mtDNA maintenance or expression. Our incomplete understanding of the underlying biology and scarcity of animal models of mtDNA disease hinders the development of curative treatments for these disorders.
The aims of the Mitochondrial Genetics programme are to engineer the mammalian mitochondrial genome to develop unique in vitro and in vivo models of mtDNA dysfunction and to exploit these models to interrogate mitochondrial genome regulation and to improve pre-clinical evaluation of treatments.
These future aims build upon considerable successes of the past quinquennium and leverage the emerging technical developments in direct DNA base editing. One way of achieving these objectives will be to generate an in vivo mouse model of single large-scale mtDNA deletions (SLSMDs) and use it, together with other existing mouse models, to refine pre-clinical gene therapy approaches aiming at elimination of heteroplasmic mutant mtDNA by programmable nucleases, and to investigate mtDNA regulation. In parallel, we will employ emerging DNA base-editing technology to install de novo mtDNA point mutations in vivo, to create a base-editor library for systematic ablation of all mtDNA-encoded protein and tRNA-coding genes in mice, and to generate mouse models mimicking the most common pathogenic mtDNA mutations (e.g. m.3243A>G). We will also continue our work on the mechanisms of mitochondrial gene expression; albeit with increasing involvement of mouse genetics and mtDNA-editing methods, focussing on knowledge gaps in quality control and decoding during mitochondrial translation and mitoribosome assembly.
The aims of the Mitochondrial Genetics programme are to engineer the mammalian mitochondrial genome to develop unique in vitro and in vivo models of mtDNA dysfunction and to exploit these models to interrogate mitochondrial genome regulation and to improve pre-clinical evaluation of treatments.
These future aims build upon considerable successes of the past quinquennium and leverage the emerging technical developments in direct DNA base editing. One way of achieving these objectives will be to generate an in vivo mouse model of single large-scale mtDNA deletions (SLSMDs) and use it, together with other existing mouse models, to refine pre-clinical gene therapy approaches aiming at elimination of heteroplasmic mutant mtDNA by programmable nucleases, and to investigate mtDNA regulation. In parallel, we will employ emerging DNA base-editing technology to install de novo mtDNA point mutations in vivo, to create a base-editor library for systematic ablation of all mtDNA-encoded protein and tRNA-coding genes in mice, and to generate mouse models mimicking the most common pathogenic mtDNA mutations (e.g. m.3243A>G). We will also continue our work on the mechanisms of mitochondrial gene expression; albeit with increasing involvement of mouse genetics and mtDNA-editing methods, focussing on knowledge gaps in quality control and decoding during mitochondrial translation and mitoribosome assembly.
Organisations
- University of Cambridge (Lead Research Organisation)
- University College London (Collaboration)
- Newcastle University (Collaboration)
- Columbia University Medical Center (Collaboration)
- University of Ghent (Collaboration)
- Carlo Besta Neurological Institute (Collaboration)
- Radboud University Nijmegen (Collaboration)
- Helmholtz Zentrum München (Collaboration)
- South Australian Clinical Genetics Service (Collaboration)
People |
ORCID iD |
Publications
Burr SP
(2023)
Cell lineage-specific mitochondrial resilience during mammalian organogenesis.
in Cell
Falabella M
(2022)
Gene therapy for primary mitochondrial diseases: experimental advances and clinical challenges.
in Nature reviews. Neurology
Keshavan N
(2024)
Gene therapy for mitochondrial disorders.
in Journal of inherited metabolic disease
Nash P
(2023)
Applications of mitochondrial gene therapy
Nash PA
(2023)
Manipulation of Murine Mitochondrial DNA Heteroplasmy with mtZFNs.
in Methods in molecular biology (Clifton, N.J.)
Páleníková P
(2023)
Protocol to study human mitochondrial ribosome using quantitative density gradient analysis by mass spectrometry and complexome profiling analysis
in STAR Protocols
Rebelo-Guiomar P
(2022)
A late-stage assembly checkpoint of the human mitochondrial ribosome large subunit.
in Nature communications
Silva-Pinheiro P
(2022)
In vivo mitochondrial base editing via adeno-associated viral delivery to mouse post-mitotic tissue.
in Nature communications
Silva-Pinheiro P
(2022)
The potential of mitochondrial genome engineering.
in Nature reviews. Genetics
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_UU_00028/1 | 01/04/2022 | 31/03/2027 | £3,998,000 | ||
MC_UU_00028/2 | Transfer | MC_UU_00028/1 | 01/04/2022 | 31/03/2027 | £3,700,000 |
MC_UU_00028/3 | Transfer | MC_UU_00028/2 | 01/04/2022 | 31/03/2027 | £3,567,000 |
MC_UU_00028/4 | Transfer | MC_UU_00028/3 | 01/04/2022 | 31/03/2027 | £3,947,000 |
MC_UU_00028/5 | Transfer | MC_UU_00028/4 | 01/04/2022 | 31/03/2027 | £3,214,000 |
MC_UU_00028/6 | Transfer | MC_UU_00028/5 | 01/04/2022 | 31/03/2027 | £3,000,000 |
MC_UU_00028/7 | Transfer | MC_UU_00028/6 | 01/04/2022 | 31/03/2027 | £1,630,000 |
MC_UU_00028/8 | Transfer | MC_UU_00028/7 | 01/04/2022 | 04/05/2025 | £433,000 |
MC_UU_00028/9 | Transfer | MC_UU_00028/8 | 01/04/2022 | 31/03/2027 | £390,000 |
Description | Focus Group: Enabling Strategic Framework for Research |
Geographic Reach | National |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | DTP studentship |
Amount | £105,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 10/2021 |
End | 09/2025 |
Description | EMBO LTF |
Amount | £100,000 (GBP) |
Organisation | European Molecular Biology Organisation |
Sector | Charity/Non Profit |
Country | Germany |
Start | 10/2021 |
End | 10/2023 |
Description | In vivo correct ion of mitochondrial genome by base editing: towards therapies for neuromuscular diseases caused by mitochondrial DNA dysfunction |
Amount | £83,000 (GBP) |
Organisation | AFM |
Sector | Private |
Country | United Kingdom |
Start | 04/2023 |
End | 03/2024 |
Description | MitoCluster - National Mouse Genetics Network |
Amount | £2,990,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 04/2022 |
End | 04/2027 |
Description | MitoFight2 |
Amount | € 600,000 (EUR) |
Organisation | Association Luigi Comini Onlus |
Sector | Charity/Non Profit |
Country | Italy |
Start | 04/2022 |
End | 03/2027 |
Description | Treatments and in vivo models for diseases caused by mitochondrial DNA deletions |
Amount | $120,000 (USD) |
Organisation | The Champ Foundation |
Sector | Charity/Non Profit |
Country | United States |
Start | 10/2021 |
End | 09/2023 |
Title | MitoKO |
Description | Library of KOs of all mouse mtDNA protein coding genes |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Year Produced | 2022 |
Provided To Others? | No |
Impact | Systematic ablation of all mouse mtDNA genes will be possible in vitro and in vivo |
Title | mtFociCounter |
Description | mtFociCounter: Quantitative and open source single-cell analysis of mitochondrial nucleoids and other foci |
Type Of Material | Data analysis technique |
Year Produced | 2022 |
Provided To Others? | Yes |
Impact | well recognized |
Description | MitoCluster within the MRC Mouse Genetics Network |
Organisation | University College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | The aims of the Mitocluster is to (i) develop a refined, comprehensive phenotyping platform for mitochondrial disease mouse models, (ii) deploy established and emerging mtDNA gene editing methods to generate novel mtDNA-engineered mouse lines, (iii) harness strong Pharma partnerships to evaluate the impact of existing and novel compounds in the whole organism and (iv) train clinical academics in mouse model and experimental design for functional genomics and develop and deliver the first courses in mtDNA dysfunction model generation and maintenance, to grow UK skills across academia and industry. We are involved in all these activities |
Collaborator Contribution | The aims of the Mitocluster is to (i) develop a refined, comprehensive phenotyping platform for mitochondrial disease mouse models, (ii) deploy established and emerging mtDNA gene editing methods to generate novel mtDNA-engineered mouse lines, (iii) harness strong Pharma partnerships to evaluate the impact of existing and novel compounds in the whole organism and (iv) train clinical academics in mouse model and experimental design for functional genomics and develop and deliver the first courses in mtDNA dysfunction model generation and maintenance, to grow UK skills across academia and industry. All partners are involved in these activities |
Impact | NIL yet |
Start Year | 2022 |
Description | Mitochondrial RNA metabolism and human disease |
Organisation | Carlo Besta Neurological Institute |
Country | Italy |
Sector | Public |
PI Contribution | We analyse molecular phenotypes associated with mutations in muclaer genes involved in mitochondrial RNA processing and post-transcriptional modification. |
Collaborator Contribution | Identification of mutations by next-generation exome sequencing in patients with combined OXPHOS defects |
Impact | Several papers e.g: Van Haute L, Dietmann S, Kremer L, Hussain S, Pearce SF, Powell CA, Rorbach J, Lantaff R, Blanco S, Sauer S, Kotzaeridou U, Hoffmann GF, Memari Y, Kolb-Kokocinski A, Durbin R, Mayr JA, Frye M, Prokisch H, Minczuk M.Deficient methylation and formylation of mt-tRNA(Met) wobble cytosine in a patient carrying mutations in NSUN3. Nat Commun. 2016 Jun 30;7:12039. doi: 10.1038/ncomms12039. Haack, T.B.*, Kopajtich, R.*, Freisinger, P.*, Wieland, T., Rorbach, J, Nicholls, T.J., Enrico Baruffini, E., Walther, A., Danhauser, K., Zimmermann, F.A., Husain, R.A., Schum, J., Mundy, H., Ferrero, I., Strom, T.M., Meitinger, T., Taylor, R.W., Minczuk, M**., Mayr, J.A., Prokisch, H.** (2013) ELAC2 Mutations Cause a Mitochondrial RNA Processing Defect Associated with Hypertrophic Cardiomyopathy. Am J Hum Genet 93, 211-223 Kopajtich, R.,* Nicholls, T.J.,* Rorbach, J.,* Freisinger, P., Mandel, H., Vanlander, A., Ghezzi, D., Carrozzo, R., Taylor, R.W., Marquard, K., Murayama, K., Wieland, T., Schwarzmayr, T., Mayr, J.A., Pearce, S. F., Powell, C. Saada, A., Ohtake, A., Invernizzi, F., Lamantea, E., Sommerville, E. W., Pyle, A., Chinnery, P. F., Crushell, E., Okazaki, Y., Kohda, M., Kishita, Y., Tokuzawa, Y., Smet, J., Régal, L., Lorber, A., Khoury, A., Zeviani, M., Strom, T. M., Meitinger, T., Bertini, E. S., Van Coster, R., Klopstock, T., Haack, T. B., Minczuk, M.,** Prokisch, H.** (-) Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis and encephalopathy Am J Hum Genet 95, 708-20 Vanlander, A.V., Menten, B., Smet, J., De Meirleir, L., Sante, T., De Paepe, B., Seneca, S., Pearce, S.F., Powell, C.A., Vergult, S., Michotte, A., De Latter, E., Vantomme, L., Minczuk, M. and Van Coster, R. (-) Two siblings with homozygous pathogenic splice site mutation in mitochondrial asparaginyl-tRNA synthetase (NARS2) Hum. Mutat Mutat 36, 222-231 Powell, C.A.*, Kopajtich, R.*, D'Souza, A.R., Rorbach, J., Dallabona, C., Donnini, C., Alston, C.L., Griffin, H., Pyle, A., Chinnery, P.F., Strom, T.M., Meitinger, T., Rodenburg, R.J., Schottmann, G., Schuelke, M., Romain, N., Haller, R., Ferrero, I., Haack, T.B., Taylor, R.W., Prokisch, H.**, Minczuk, M. (2015) Mutations in TRMT5 cause a defect in post-transcriptional modification of mitochondrial tRNA associated with multiple respiratory-chain deficiencies. Am J Hum Genet. 97,319-328 Coughlin, C.R. Scharer, G.H., Friederich, M.W., Yu, H.C., Geiger, E.A., Creadon-Swindell, G., Collins, A.E., Vanlander, A.V., Coster, R.V., Powell, C.A., Swanson, M.A., Minczuk, M., Van Hove, J.L., Shaikh, T.H. (2015) Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder. J Med Genet. 52,532-540 and more |
Start Year | 2011 |
Description | Mitochondrial RNA metabolism and human disease |
Organisation | Columbia University Medical Center |
Country | United States |
Sector | Academic/University |
PI Contribution | We analyse molecular phenotypes associated with mutations in muclaer genes involved in mitochondrial RNA processing and post-transcriptional modification. |
Collaborator Contribution | Identification of mutations by next-generation exome sequencing in patients with combined OXPHOS defects |
Impact | Several papers e.g: Van Haute L, Dietmann S, Kremer L, Hussain S, Pearce SF, Powell CA, Rorbach J, Lantaff R, Blanco S, Sauer S, Kotzaeridou U, Hoffmann GF, Memari Y, Kolb-Kokocinski A, Durbin R, Mayr JA, Frye M, Prokisch H, Minczuk M.Deficient methylation and formylation of mt-tRNA(Met) wobble cytosine in a patient carrying mutations in NSUN3. Nat Commun. 2016 Jun 30;7:12039. doi: 10.1038/ncomms12039. Haack, T.B.*, Kopajtich, R.*, Freisinger, P.*, Wieland, T., Rorbach, J, Nicholls, T.J., Enrico Baruffini, E., Walther, A., Danhauser, K., Zimmermann, F.A., Husain, R.A., Schum, J., Mundy, H., Ferrero, I., Strom, T.M., Meitinger, T., Taylor, R.W., Minczuk, M**., Mayr, J.A., Prokisch, H.** (2013) ELAC2 Mutations Cause a Mitochondrial RNA Processing Defect Associated with Hypertrophic Cardiomyopathy. Am J Hum Genet 93, 211-223 Kopajtich, R.,* Nicholls, T.J.,* Rorbach, J.,* Freisinger, P., Mandel, H., Vanlander, A., Ghezzi, D., Carrozzo, R., Taylor, R.W., Marquard, K., Murayama, K., Wieland, T., Schwarzmayr, T., Mayr, J.A., Pearce, S. F., Powell, C. Saada, A., Ohtake, A., Invernizzi, F., Lamantea, E., Sommerville, E. W., Pyle, A., Chinnery, P. F., Crushell, E., Okazaki, Y., Kohda, M., Kishita, Y., Tokuzawa, Y., Smet, J., Régal, L., Lorber, A., Khoury, A., Zeviani, M., Strom, T. M., Meitinger, T., Bertini, E. S., Van Coster, R., Klopstock, T., Haack, T. B., Minczuk, M.,** Prokisch, H.** (-) Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis and encephalopathy Am J Hum Genet 95, 708-20 Vanlander, A.V., Menten, B., Smet, J., De Meirleir, L., Sante, T., De Paepe, B., Seneca, S., Pearce, S.F., Powell, C.A., Vergult, S., Michotte, A., De Latter, E., Vantomme, L., Minczuk, M. and Van Coster, R. (-) Two siblings with homozygous pathogenic splice site mutation in mitochondrial asparaginyl-tRNA synthetase (NARS2) Hum. Mutat Mutat 36, 222-231 Powell, C.A.*, Kopajtich, R.*, D'Souza, A.R., Rorbach, J., Dallabona, C., Donnini, C., Alston, C.L., Griffin, H., Pyle, A., Chinnery, P.F., Strom, T.M., Meitinger, T., Rodenburg, R.J., Schottmann, G., Schuelke, M., Romain, N., Haller, R., Ferrero, I., Haack, T.B., Taylor, R.W., Prokisch, H.**, Minczuk, M. (2015) Mutations in TRMT5 cause a defect in post-transcriptional modification of mitochondrial tRNA associated with multiple respiratory-chain deficiencies. Am J Hum Genet. 97,319-328 Coughlin, C.R. Scharer, G.H., Friederich, M.W., Yu, H.C., Geiger, E.A., Creadon-Swindell, G., Collins, A.E., Vanlander, A.V., Coster, R.V., Powell, C.A., Swanson, M.A., Minczuk, M., Van Hove, J.L., Shaikh, T.H. (2015) Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder. J Med Genet. 52,532-540 and more |
Start Year | 2011 |
Description | Mitochondrial RNA metabolism and human disease |
Organisation | Helmholtz Zentrum München |
Department | Institute of Human Genetics |
Country | Germany |
Sector | Academic/University |
PI Contribution | We analyse molecular phenotypes associated with mutations in muclaer genes involved in mitochondrial RNA processing and post-transcriptional modification. |
Collaborator Contribution | Identification of mutations by next-generation exome sequencing in patients with combined OXPHOS defects |
Impact | Several papers e.g: Van Haute L, Dietmann S, Kremer L, Hussain S, Pearce SF, Powell CA, Rorbach J, Lantaff R, Blanco S, Sauer S, Kotzaeridou U, Hoffmann GF, Memari Y, Kolb-Kokocinski A, Durbin R, Mayr JA, Frye M, Prokisch H, Minczuk M.Deficient methylation and formylation of mt-tRNA(Met) wobble cytosine in a patient carrying mutations in NSUN3. Nat Commun. 2016 Jun 30;7:12039. doi: 10.1038/ncomms12039. Haack, T.B.*, Kopajtich, R.*, Freisinger, P.*, Wieland, T., Rorbach, J, Nicholls, T.J., Enrico Baruffini, E., Walther, A., Danhauser, K., Zimmermann, F.A., Husain, R.A., Schum, J., Mundy, H., Ferrero, I., Strom, T.M., Meitinger, T., Taylor, R.W., Minczuk, M**., Mayr, J.A., Prokisch, H.** (2013) ELAC2 Mutations Cause a Mitochondrial RNA Processing Defect Associated with Hypertrophic Cardiomyopathy. Am J Hum Genet 93, 211-223 Kopajtich, R.,* Nicholls, T.J.,* Rorbach, J.,* Freisinger, P., Mandel, H., Vanlander, A., Ghezzi, D., Carrozzo, R., Taylor, R.W., Marquard, K., Murayama, K., Wieland, T., Schwarzmayr, T., Mayr, J.A., Pearce, S. F., Powell, C. Saada, A., Ohtake, A., Invernizzi, F., Lamantea, E., Sommerville, E. W., Pyle, A., Chinnery, P. F., Crushell, E., Okazaki, Y., Kohda, M., Kishita, Y., Tokuzawa, Y., Smet, J., Régal, L., Lorber, A., Khoury, A., Zeviani, M., Strom, T. M., Meitinger, T., Bertini, E. S., Van Coster, R., Klopstock, T., Haack, T. B., Minczuk, M.,** Prokisch, H.** (-) Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis and encephalopathy Am J Hum Genet 95, 708-20 Vanlander, A.V., Menten, B., Smet, J., De Meirleir, L., Sante, T., De Paepe, B., Seneca, S., Pearce, S.F., Powell, C.A., Vergult, S., Michotte, A., De Latter, E., Vantomme, L., Minczuk, M. and Van Coster, R. (-) Two siblings with homozygous pathogenic splice site mutation in mitochondrial asparaginyl-tRNA synthetase (NARS2) Hum. Mutat Mutat 36, 222-231 Powell, C.A.*, Kopajtich, R.*, D'Souza, A.R., Rorbach, J., Dallabona, C., Donnini, C., Alston, C.L., Griffin, H., Pyle, A., Chinnery, P.F., Strom, T.M., Meitinger, T., Rodenburg, R.J., Schottmann, G., Schuelke, M., Romain, N., Haller, R., Ferrero, I., Haack, T.B., Taylor, R.W., Prokisch, H.**, Minczuk, M. (2015) Mutations in TRMT5 cause a defect in post-transcriptional modification of mitochondrial tRNA associated with multiple respiratory-chain deficiencies. Am J Hum Genet. 97,319-328 Coughlin, C.R. Scharer, G.H., Friederich, M.W., Yu, H.C., Geiger, E.A., Creadon-Swindell, G., Collins, A.E., Vanlander, A.V., Coster, R.V., Powell, C.A., Swanson, M.A., Minczuk, M., Van Hove, J.L., Shaikh, T.H. (2015) Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder. J Med Genet. 52,532-540 and more |
Start Year | 2011 |
Description | Mitochondrial RNA metabolism and human disease |
Organisation | Newcastle University |
Department | School of Biomedical Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We analyse molecular phenotypes associated with mutations in muclaer genes involved in mitochondrial RNA processing and post-transcriptional modification. |
Collaborator Contribution | Identification of mutations by next-generation exome sequencing in patients with combined OXPHOS defects |
Impact | Several papers e.g: Van Haute L, Dietmann S, Kremer L, Hussain S, Pearce SF, Powell CA, Rorbach J, Lantaff R, Blanco S, Sauer S, Kotzaeridou U, Hoffmann GF, Memari Y, Kolb-Kokocinski A, Durbin R, Mayr JA, Frye M, Prokisch H, Minczuk M.Deficient methylation and formylation of mt-tRNA(Met) wobble cytosine in a patient carrying mutations in NSUN3. Nat Commun. 2016 Jun 30;7:12039. doi: 10.1038/ncomms12039. Haack, T.B.*, Kopajtich, R.*, Freisinger, P.*, Wieland, T., Rorbach, J, Nicholls, T.J., Enrico Baruffini, E., Walther, A., Danhauser, K., Zimmermann, F.A., Husain, R.A., Schum, J., Mundy, H., Ferrero, I., Strom, T.M., Meitinger, T., Taylor, R.W., Minczuk, M**., Mayr, J.A., Prokisch, H.** (2013) ELAC2 Mutations Cause a Mitochondrial RNA Processing Defect Associated with Hypertrophic Cardiomyopathy. Am J Hum Genet 93, 211-223 Kopajtich, R.,* Nicholls, T.J.,* Rorbach, J.,* Freisinger, P., Mandel, H., Vanlander, A., Ghezzi, D., Carrozzo, R., Taylor, R.W., Marquard, K., Murayama, K., Wieland, T., Schwarzmayr, T., Mayr, J.A., Pearce, S. F., Powell, C. Saada, A., Ohtake, A., Invernizzi, F., Lamantea, E., Sommerville, E. W., Pyle, A., Chinnery, P. F., Crushell, E., Okazaki, Y., Kohda, M., Kishita, Y., Tokuzawa, Y., Smet, J., Régal, L., Lorber, A., Khoury, A., Zeviani, M., Strom, T. M., Meitinger, T., Bertini, E. S., Van Coster, R., Klopstock, T., Haack, T. B., Minczuk, M.,** Prokisch, H.** (-) Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis and encephalopathy Am J Hum Genet 95, 708-20 Vanlander, A.V., Menten, B., Smet, J., De Meirleir, L., Sante, T., De Paepe, B., Seneca, S., Pearce, S.F., Powell, C.A., Vergult, S., Michotte, A., De Latter, E., Vantomme, L., Minczuk, M. and Van Coster, R. (-) Two siblings with homozygous pathogenic splice site mutation in mitochondrial asparaginyl-tRNA synthetase (NARS2) Hum. Mutat Mutat 36, 222-231 Powell, C.A.*, Kopajtich, R.*, D'Souza, A.R., Rorbach, J., Dallabona, C., Donnini, C., Alston, C.L., Griffin, H., Pyle, A., Chinnery, P.F., Strom, T.M., Meitinger, T., Rodenburg, R.J., Schottmann, G., Schuelke, M., Romain, N., Haller, R., Ferrero, I., Haack, T.B., Taylor, R.W., Prokisch, H.**, Minczuk, M. (2015) Mutations in TRMT5 cause a defect in post-transcriptional modification of mitochondrial tRNA associated with multiple respiratory-chain deficiencies. Am J Hum Genet. 97,319-328 Coughlin, C.R. Scharer, G.H., Friederich, M.W., Yu, H.C., Geiger, E.A., Creadon-Swindell, G., Collins, A.E., Vanlander, A.V., Coster, R.V., Powell, C.A., Swanson, M.A., Minczuk, M., Van Hove, J.L., Shaikh, T.H. (2015) Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder. J Med Genet. 52,532-540 and more |
Start Year | 2011 |
Description | Mitochondrial RNA metabolism and human disease |
Organisation | Radboud University Nijmegen |
Country | Netherlands |
Sector | Academic/University |
PI Contribution | We analyse molecular phenotypes associated with mutations in muclaer genes involved in mitochondrial RNA processing and post-transcriptional modification. |
Collaborator Contribution | Identification of mutations by next-generation exome sequencing in patients with combined OXPHOS defects |
Impact | Several papers e.g: Van Haute L, Dietmann S, Kremer L, Hussain S, Pearce SF, Powell CA, Rorbach J, Lantaff R, Blanco S, Sauer S, Kotzaeridou U, Hoffmann GF, Memari Y, Kolb-Kokocinski A, Durbin R, Mayr JA, Frye M, Prokisch H, Minczuk M.Deficient methylation and formylation of mt-tRNA(Met) wobble cytosine in a patient carrying mutations in NSUN3. Nat Commun. 2016 Jun 30;7:12039. doi: 10.1038/ncomms12039. Haack, T.B.*, Kopajtich, R.*, Freisinger, P.*, Wieland, T., Rorbach, J, Nicholls, T.J., Enrico Baruffini, E., Walther, A., Danhauser, K., Zimmermann, F.A., Husain, R.A., Schum, J., Mundy, H., Ferrero, I., Strom, T.M., Meitinger, T., Taylor, R.W., Minczuk, M**., Mayr, J.A., Prokisch, H.** (2013) ELAC2 Mutations Cause a Mitochondrial RNA Processing Defect Associated with Hypertrophic Cardiomyopathy. Am J Hum Genet 93, 211-223 Kopajtich, R.,* Nicholls, T.J.,* Rorbach, J.,* Freisinger, P., Mandel, H., Vanlander, A., Ghezzi, D., Carrozzo, R., Taylor, R.W., Marquard, K., Murayama, K., Wieland, T., Schwarzmayr, T., Mayr, J.A., Pearce, S. F., Powell, C. Saada, A., Ohtake, A., Invernizzi, F., Lamantea, E., Sommerville, E. W., Pyle, A., Chinnery, P. F., Crushell, E., Okazaki, Y., Kohda, M., Kishita, Y., Tokuzawa, Y., Smet, J., Régal, L., Lorber, A., Khoury, A., Zeviani, M., Strom, T. M., Meitinger, T., Bertini, E. S., Van Coster, R., Klopstock, T., Haack, T. B., Minczuk, M.,** Prokisch, H.** (-) Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis and encephalopathy Am J Hum Genet 95, 708-20 Vanlander, A.V., Menten, B., Smet, J., De Meirleir, L., Sante, T., De Paepe, B., Seneca, S., Pearce, S.F., Powell, C.A., Vergult, S., Michotte, A., De Latter, E., Vantomme, L., Minczuk, M. and Van Coster, R. (-) Two siblings with homozygous pathogenic splice site mutation in mitochondrial asparaginyl-tRNA synthetase (NARS2) Hum. Mutat Mutat 36, 222-231 Powell, C.A.*, Kopajtich, R.*, D'Souza, A.R., Rorbach, J., Dallabona, C., Donnini, C., Alston, C.L., Griffin, H., Pyle, A., Chinnery, P.F., Strom, T.M., Meitinger, T., Rodenburg, R.J., Schottmann, G., Schuelke, M., Romain, N., Haller, R., Ferrero, I., Haack, T.B., Taylor, R.W., Prokisch, H.**, Minczuk, M. (2015) Mutations in TRMT5 cause a defect in post-transcriptional modification of mitochondrial tRNA associated with multiple respiratory-chain deficiencies. Am J Hum Genet. 97,319-328 Coughlin, C.R. Scharer, G.H., Friederich, M.W., Yu, H.C., Geiger, E.A., Creadon-Swindell, G., Collins, A.E., Vanlander, A.V., Coster, R.V., Powell, C.A., Swanson, M.A., Minczuk, M., Van Hove, J.L., Shaikh, T.H. (2015) Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder. J Med Genet. 52,532-540 and more |
Start Year | 2011 |
Description | Mitochondrial RNA metabolism and human disease |
Organisation | South Australian Clinical Genetics Service |
Country | Australia |
Sector | Hospitals |
PI Contribution | We analyse molecular phenotypes associated with mutations in muclaer genes involved in mitochondrial RNA processing and post-transcriptional modification. |
Collaborator Contribution | Identification of mutations by next-generation exome sequencing in patients with combined OXPHOS defects |
Impact | Several papers e.g: Van Haute L, Dietmann S, Kremer L, Hussain S, Pearce SF, Powell CA, Rorbach J, Lantaff R, Blanco S, Sauer S, Kotzaeridou U, Hoffmann GF, Memari Y, Kolb-Kokocinski A, Durbin R, Mayr JA, Frye M, Prokisch H, Minczuk M.Deficient methylation and formylation of mt-tRNA(Met) wobble cytosine in a patient carrying mutations in NSUN3. Nat Commun. 2016 Jun 30;7:12039. doi: 10.1038/ncomms12039. Haack, T.B.*, Kopajtich, R.*, Freisinger, P.*, Wieland, T., Rorbach, J, Nicholls, T.J., Enrico Baruffini, E., Walther, A., Danhauser, K., Zimmermann, F.A., Husain, R.A., Schum, J., Mundy, H., Ferrero, I., Strom, T.M., Meitinger, T., Taylor, R.W., Minczuk, M**., Mayr, J.A., Prokisch, H.** (2013) ELAC2 Mutations Cause a Mitochondrial RNA Processing Defect Associated with Hypertrophic Cardiomyopathy. Am J Hum Genet 93, 211-223 Kopajtich, R.,* Nicholls, T.J.,* Rorbach, J.,* Freisinger, P., Mandel, H., Vanlander, A., Ghezzi, D., Carrozzo, R., Taylor, R.W., Marquard, K., Murayama, K., Wieland, T., Schwarzmayr, T., Mayr, J.A., Pearce, S. F., Powell, C. Saada, A., Ohtake, A., Invernizzi, F., Lamantea, E., Sommerville, E. W., Pyle, A., Chinnery, P. F., Crushell, E., Okazaki, Y., Kohda, M., Kishita, Y., Tokuzawa, Y., Smet, J., Régal, L., Lorber, A., Khoury, A., Zeviani, M., Strom, T. M., Meitinger, T., Bertini, E. S., Van Coster, R., Klopstock, T., Haack, T. B., Minczuk, M.,** Prokisch, H.** (-) Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis and encephalopathy Am J Hum Genet 95, 708-20 Vanlander, A.V., Menten, B., Smet, J., De Meirleir, L., Sante, T., De Paepe, B., Seneca, S., Pearce, S.F., Powell, C.A., Vergult, S., Michotte, A., De Latter, E., Vantomme, L., Minczuk, M. and Van Coster, R. (-) Two siblings with homozygous pathogenic splice site mutation in mitochondrial asparaginyl-tRNA synthetase (NARS2) Hum. Mutat Mutat 36, 222-231 Powell, C.A.*, Kopajtich, R.*, D'Souza, A.R., Rorbach, J., Dallabona, C., Donnini, C., Alston, C.L., Griffin, H., Pyle, A., Chinnery, P.F., Strom, T.M., Meitinger, T., Rodenburg, R.J., Schottmann, G., Schuelke, M., Romain, N., Haller, R., Ferrero, I., Haack, T.B., Taylor, R.W., Prokisch, H.**, Minczuk, M. (2015) Mutations in TRMT5 cause a defect in post-transcriptional modification of mitochondrial tRNA associated with multiple respiratory-chain deficiencies. Am J Hum Genet. 97,319-328 Coughlin, C.R. Scharer, G.H., Friederich, M.W., Yu, H.C., Geiger, E.A., Creadon-Swindell, G., Collins, A.E., Vanlander, A.V., Coster, R.V., Powell, C.A., Swanson, M.A., Minczuk, M., Van Hove, J.L., Shaikh, T.H. (2015) Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder. J Med Genet. 52,532-540 and more |
Start Year | 2011 |
Description | Mitochondrial RNA metabolism and human disease |
Organisation | University College London |
Department | Faculty of Medical Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We analyse molecular phenotypes associated with mutations in muclaer genes involved in mitochondrial RNA processing and post-transcriptional modification. |
Collaborator Contribution | Identification of mutations by next-generation exome sequencing in patients with combined OXPHOS defects |
Impact | Several papers e.g: Van Haute L, Dietmann S, Kremer L, Hussain S, Pearce SF, Powell CA, Rorbach J, Lantaff R, Blanco S, Sauer S, Kotzaeridou U, Hoffmann GF, Memari Y, Kolb-Kokocinski A, Durbin R, Mayr JA, Frye M, Prokisch H, Minczuk M.Deficient methylation and formylation of mt-tRNA(Met) wobble cytosine in a patient carrying mutations in NSUN3. Nat Commun. 2016 Jun 30;7:12039. doi: 10.1038/ncomms12039. Haack, T.B.*, Kopajtich, R.*, Freisinger, P.*, Wieland, T., Rorbach, J, Nicholls, T.J., Enrico Baruffini, E., Walther, A., Danhauser, K., Zimmermann, F.A., Husain, R.A., Schum, J., Mundy, H., Ferrero, I., Strom, T.M., Meitinger, T., Taylor, R.W., Minczuk, M**., Mayr, J.A., Prokisch, H.** (2013) ELAC2 Mutations Cause a Mitochondrial RNA Processing Defect Associated with Hypertrophic Cardiomyopathy. Am J Hum Genet 93, 211-223 Kopajtich, R.,* Nicholls, T.J.,* Rorbach, J.,* Freisinger, P., Mandel, H., Vanlander, A., Ghezzi, D., Carrozzo, R., Taylor, R.W., Marquard, K., Murayama, K., Wieland, T., Schwarzmayr, T., Mayr, J.A., Pearce, S. F., Powell, C. Saada, A., Ohtake, A., Invernizzi, F., Lamantea, E., Sommerville, E. W., Pyle, A., Chinnery, P. F., Crushell, E., Okazaki, Y., Kohda, M., Kishita, Y., Tokuzawa, Y., Smet, J., Régal, L., Lorber, A., Khoury, A., Zeviani, M., Strom, T. M., Meitinger, T., Bertini, E. S., Van Coster, R., Klopstock, T., Haack, T. B., Minczuk, M.,** Prokisch, H.** (-) Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis and encephalopathy Am J Hum Genet 95, 708-20 Vanlander, A.V., Menten, B., Smet, J., De Meirleir, L., Sante, T., De Paepe, B., Seneca, S., Pearce, S.F., Powell, C.A., Vergult, S., Michotte, A., De Latter, E., Vantomme, L., Minczuk, M. and Van Coster, R. (-) Two siblings with homozygous pathogenic splice site mutation in mitochondrial asparaginyl-tRNA synthetase (NARS2) Hum. Mutat Mutat 36, 222-231 Powell, C.A.*, Kopajtich, R.*, D'Souza, A.R., Rorbach, J., Dallabona, C., Donnini, C., Alston, C.L., Griffin, H., Pyle, A., Chinnery, P.F., Strom, T.M., Meitinger, T., Rodenburg, R.J., Schottmann, G., Schuelke, M., Romain, N., Haller, R., Ferrero, I., Haack, T.B., Taylor, R.W., Prokisch, H.**, Minczuk, M. (2015) Mutations in TRMT5 cause a defect in post-transcriptional modification of mitochondrial tRNA associated with multiple respiratory-chain deficiencies. Am J Hum Genet. 97,319-328 Coughlin, C.R. Scharer, G.H., Friederich, M.W., Yu, H.C., Geiger, E.A., Creadon-Swindell, G., Collins, A.E., Vanlander, A.V., Coster, R.V., Powell, C.A., Swanson, M.A., Minczuk, M., Van Hove, J.L., Shaikh, T.H. (2015) Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder. J Med Genet. 52,532-540 and more |
Start Year | 2011 |
Description | Mitochondrial RNA metabolism and human disease |
Organisation | University of Ghent |
Country | Belgium |
Sector | Academic/University |
PI Contribution | We analyse molecular phenotypes associated with mutations in muclaer genes involved in mitochondrial RNA processing and post-transcriptional modification. |
Collaborator Contribution | Identification of mutations by next-generation exome sequencing in patients with combined OXPHOS defects |
Impact | Several papers e.g: Van Haute L, Dietmann S, Kremer L, Hussain S, Pearce SF, Powell CA, Rorbach J, Lantaff R, Blanco S, Sauer S, Kotzaeridou U, Hoffmann GF, Memari Y, Kolb-Kokocinski A, Durbin R, Mayr JA, Frye M, Prokisch H, Minczuk M.Deficient methylation and formylation of mt-tRNA(Met) wobble cytosine in a patient carrying mutations in NSUN3. Nat Commun. 2016 Jun 30;7:12039. doi: 10.1038/ncomms12039. Haack, T.B.*, Kopajtich, R.*, Freisinger, P.*, Wieland, T., Rorbach, J, Nicholls, T.J., Enrico Baruffini, E., Walther, A., Danhauser, K., Zimmermann, F.A., Husain, R.A., Schum, J., Mundy, H., Ferrero, I., Strom, T.M., Meitinger, T., Taylor, R.W., Minczuk, M**., Mayr, J.A., Prokisch, H.** (2013) ELAC2 Mutations Cause a Mitochondrial RNA Processing Defect Associated with Hypertrophic Cardiomyopathy. Am J Hum Genet 93, 211-223 Kopajtich, R.,* Nicholls, T.J.,* Rorbach, J.,* Freisinger, P., Mandel, H., Vanlander, A., Ghezzi, D., Carrozzo, R., Taylor, R.W., Marquard, K., Murayama, K., Wieland, T., Schwarzmayr, T., Mayr, J.A., Pearce, S. F., Powell, C. Saada, A., Ohtake, A., Invernizzi, F., Lamantea, E., Sommerville, E. W., Pyle, A., Chinnery, P. F., Crushell, E., Okazaki, Y., Kohda, M., Kishita, Y., Tokuzawa, Y., Smet, J., Régal, L., Lorber, A., Khoury, A., Zeviani, M., Strom, T. M., Meitinger, T., Bertini, E. S., Van Coster, R., Klopstock, T., Haack, T. B., Minczuk, M.,** Prokisch, H.** (-) Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis and encephalopathy Am J Hum Genet 95, 708-20 Vanlander, A.V., Menten, B., Smet, J., De Meirleir, L., Sante, T., De Paepe, B., Seneca, S., Pearce, S.F., Powell, C.A., Vergult, S., Michotte, A., De Latter, E., Vantomme, L., Minczuk, M. and Van Coster, R. (-) Two siblings with homozygous pathogenic splice site mutation in mitochondrial asparaginyl-tRNA synthetase (NARS2) Hum. Mutat Mutat 36, 222-231 Powell, C.A.*, Kopajtich, R.*, D'Souza, A.R., Rorbach, J., Dallabona, C., Donnini, C., Alston, C.L., Griffin, H., Pyle, A., Chinnery, P.F., Strom, T.M., Meitinger, T., Rodenburg, R.J., Schottmann, G., Schuelke, M., Romain, N., Haller, R., Ferrero, I., Haack, T.B., Taylor, R.W., Prokisch, H.**, Minczuk, M. (2015) Mutations in TRMT5 cause a defect in post-transcriptional modification of mitochondrial tRNA associated with multiple respiratory-chain deficiencies. Am J Hum Genet. 97,319-328 Coughlin, C.R. Scharer, G.H., Friederich, M.W., Yu, H.C., Geiger, E.A., Creadon-Swindell, G., Collins, A.E., Vanlander, A.V., Coster, R.V., Powell, C.A., Swanson, M.A., Minczuk, M., Van Hove, J.L., Shaikh, T.H. (2015) Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder. J Med Genet. 52,532-540 and more |
Start Year | 2011 |
Title | ??????????? |
Description | The present disclosure relates to the field of genome engineering, particularly targeted genetic modification of mitochondrial DNA (mtDNA). |
IP Reference | CN112805012 |
Protection | Patent / Patent application |
Year Protection Granted | 2021 |
Licensed | Commercial In Confidence |
Impact | The present disclosure relates to the field of genome engineering, particularly targeted genetic modification of mitochondrial DNA (mtDNA). |
Title | METHODS OF OPTIMISING EXPRESSION AND DELIVERY OF MITOCHONDRIAL PROTEINS |
Description | The invention relates to methods for the simultaneous expression and delivery to mitochondria of two or more proteins using a single expression vector. Also described are the expression vectors and host cells comprising the vectors. Where the proteins are genome editing reagents, the invention also relates to the use of the expression vectors to alter levels of mitochondrial heteroplasmy and treat mitochondrial disorders. |
IP Reference | US2022340930 |
Protection | Patent / Patent application |
Year Protection Granted | 2022 |
Licensed | Yes |
Impact | MITOKO |
Description | Access Students from Cambridge Regional College |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | 11 Access students from Cambridge Regional College visited the MBU for a "Biology Masterclass", a visit to the fly laboratory and a "meet the scientists" session, where hands-on "festival" activities were available. |
Year(s) Of Engagement Activity | 2022 |
Description | RAREfest 2022 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | MBU volunteers showcased the Unit's research via posters, discussions and hands-on activities. The event was organised by the Rare Disease Network. It is held every two years and is aimed at providing a platform of communication for patients, their families and carers, healthcare professionals/providers and researchers. Video footage is available here: https://www.youtube.com/@mrcmitochondrialbiologyun i211/playlists |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.camraredisease.org/rarefest22/ |
Description | Website and social media |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | My research is promoted on the MBU's website and via social media channels, such as Facebook and Twitter. This leads to various forms of engagement - increased awareness, requests for further information, potential collaborations etc. |
Year(s) Of Engagement Activity | 2022,2023 |
URL | https://www.mrc-mbu.cam.ac.uk/research-groups/minczuk-group |