Minczuk Group

Mitochondrial genetics: Mitochondrial genome engineering to unravel the genetic links between mitochondrial gene regulation and human disease for future therapies

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 cannot 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.

Selected Publications

Nash PA, Turner KM, Powell CA, Van Haute L, Silva-Pinheiro P, Bubeck F, Wiedtke E, Marques E, Ryan DG, Grimm D, Gammage PA, Minczuk M. (2025)
Clinically translatable mitochondrial gene therapy in muscle using tandem mtZFN architecture.
EMBO Mol Med.  doi: 10.1038/s44321-025-00231-5.

Silva-Pinheiro P, Mutti CD, Van Haute L, Powell CA, Nash PA, Turner K & Minczuk M (2023)
A library of base editors for precise ablation of all protein-coding genes in the mouse mitochondrial genome.
Nature Biomed Eng. 7,  692–703

Burr SP, Klimm F, Glynos A, Prater M, Sendon P, Nash P, Powell CA, Simard ML, Bonekamp NA, Charl J, Diaz H, Bozhilova LV, Nie Y, Zhang H, Frison M, Falkenberg M, Jones N, Minczuk M, Stewart JB & Chinnery PF (2023)
Cell lineage-specific mitochondrial resilience during mammalian organogenesis.
Cell  186, 1212–1229

Willis JCW, Silva-Pinheiro P, Widdup L, Minczuk M, Liu DR. (2022)
Compact zinc finger base editors that edit mitochondrial or nuclear DNA in vitro and in vivo.
Nature Commun. 13:7204

Rebelo-Guiomar P, Pellegrino S, Dent KC, Sas-Chen A, Miller-Fleming L, Garone C, Van Haute L, Rogan JF, Dinan A, Firth AE, Andrews B, Whitworth AJ, Schwartz S, Warren AJ & Minczuk M (2022)
A late-stage assembly checkpoint of the human mitochondrial ribosome large subunit.
Nature Commun. 13, 929

Silva-Pinheiro P, Nash PA, Van Haute L, Mutti CD, Turner K & Minczuk M (2022)
In vivo mitochondrial base editing via adeno-associated viral delivery to mouse post-mitotic tissue.
Nature Commun. 13, 750

Silva-Pinheiro P & Minczuk M (2021)
The potential of mitochondrial genome engineering
Nature Rev Genet, 23, 199-214

Desai N, Yang H, Chandrasekaran V, Kazi R, Minczuk M & Ramakrishnan V (2020)
Elongational stalling activates mitoribosome-associated quality control.
Science 370, 1105 - 1110

Gammage PA, Viscomi C, Simard M-L, Costa ASH, Gaude E, Powell CA, Van Haute L, McCann BJ, Rebelo-Guiomar P, Cerutti R, Zhang L, Rebar EJ, Zeviani M, Frezza C, Stewart JB & Minczuk M (2018)
Genome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo.
Nature Medicine 24, 1691-1695

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