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Unravelling the effects of mitochondrial replacement therapy on mtDNA transmission (Professor Dagan Wells)

PROJECT TITLE

Unravelling the effects of mitochondrial replacement therapy on mtDNA transmission

SUPERVISORS

DESCRIPTION OF PROJECT

Mitochondrial replacement therapy (MRT) is a translational therapy in clinical trials, aimed at (i) preventing mitochondrial DNA (mtDNA) disease transmission and (ii) treating female infertility. Human oocytes carry ~100,000 mtDNA copies, typically identical (homoplasmy). In mtDNA diseases, both mutated and normal mtDNA coexist (heteroplasmy). MRT involves transferring the mother’s nuclear DNA into a donor egg that contains healthy mitochondria but no nucleus. Resulting embryos usually contain <5% of maternal mtDNA.

DW generated data at the Juno diagnostic facility showing that although MRT initially reduced maternal mtDNA to ~2%, heteroplasmy rose to >50% in 1 of 6 offspring. This may result from differential mtDNA replication or altered mitophagy. A progressive shift could cause immune alterations and accelerated ageing, as seen in mouse models (Lechuga-Vieco et al., Circulation 2022; Leng H. et al., bioRxiv 2025), and may impact MRT efficacy in preventing mtDNA disease transmission. We aim to investigate the cause and effect of this heteroplasmic shift, examine agents that can modify it, and comprehend resulting alterations in cellular function.

In collaboration with Dr. Lechuga-Vieco, we will perform metabolic immune profiling by spectral flow cytometry on PBMCs from offspring in Prof. Wells’ study, comparing them to age-matched non-MRT and parental controls. We will investigate how mitophagy influences immune cell function by analysing transcriptional programs, cytokine production, and inflammatory responses using single-cell RNA sequencing. This analysis will uncover the potential link between mitochondrial quality control and immune regulation.

Using embryonic and adult fibroblasts, and PBMCs from a well-established preclinical model of mtDNA heteroplasmy, we will quantify mitophagy activity and assess the replicative dynamics of the two mtDNA variants. In parallel, we will screen for small-molecule modulators of mitophagy that could potentially alter heteroplasmy levels, with the aim of identifying therapeutic strategies to control mtDNA composition in affected cells.

TRAINING OPPORTUNITIES

This UKRI-funded scheme combines research training with an industrial placement (Juno Genetics).

This project is multi-disciplinary spanning two groups based in WRH, and Brent Ryan’s in the Kavli Institute for Nanoscience Discovery with strong links to the Specialist Mitochondrial Disorders Service (NHS HSS) within Genomic Medicine and the Target Discovery Institute. Ana-Victoria Lechuga Vieco (Institute for Research in Biomedicine (IRB Barcelona, Spain) / Ageing and Metabolism Department) is an External Visitor at the University of Oxford (NDORMS, Kennedy Institute of Rheumathology). The student will be based in WRH at the Women’s Centre within JP’s group for the mitophagy studies .and will have close links with Brent Ryan’s group, based in the Kalvi.

The student will be trained in immunophenotyping in Ana-Victoria Lechuga Vieco’s group, including high content fluorescence microscopy and confocal/STED microscopy, ELISA analyses, primary cell cultures and spectral flow cytometry. Additional techniques may include high-throughput sequencing (targeted, exome, whole genome, single cell transcriptomics), small particle FACs, western blotting and immunoprecipitation.  The student will attend the Methods and Techniques Course including statistics. The Medical Sciences Division's Skills Training Programme offers a range of generic skill-enhancing courses, designed to enhance personal effectiveness, thesis writing and presentation skills, research organization and engagement, as well as one's influence within the scientific community.

During a 3-month internship, the student will gain hands-on experience in Juno Genetics, a high-throughput diagnostic lab serving international clients.

Funding Information

Oxford-MRC Enterprise (iCASE) Studentships (ICase) studentship competition.

HOW TO APPLY

To apply for this research degree, please click here.