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.
Biography
Michal obtained a Master’s degree in Biotechnology (1999) and PhD in Biological Sciences (2003) from the University of Warsaw, Poland, carrying out research in the Institute of Genetics and Biotechnology. From 2004–2007 he was an FEBS Postdoctoral Fellow in the group of Aaron Klug at Medical Research Council (MRC), Laboratory of Molecular Biology, Cambridge. Michal joined the MRC Mitochondrial Biology Unit as an Investigator Scientist (2007) and in 2009 he became a MRC Investigator. In 2023 he was appointed Professor of Mitochondrial Genetics in the Department of Clinical Neurosciences, University of Cambridge. Throughout his career Michal has received numerous awards and personal fellowships, including the Prime Minister Prize for his PhD thesis, Award of the Foundation for Polish Science, EMBO and FEBS Fellowships, served as an editor of several journals and books and organised a number of scientific conferences. More recently, Michal has co-founded Pretzel Therapeutics, a start-up biotechnology company that focuses on the development of therapies to treat unmet needs in diseases driven by mitochondrial dysfunction.
Publications
Selected Publications
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
Cell lineage-specific mitochondrial resilience during mammalian organogenesis.
Cell 186, 1212–1229
(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
Elongational stalling activates mitoribosome-associated quality control.
Science 370, 1105 - 1110
Genome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo.
Nature Medicine 24, 1691-1695