About the Project
Mutations in mitochondrial DNA (mtDNA) are the most common cause of inherited mitochondrial disease and are increasingly implicated in common age-related conditions including neurodegeneration. The pathogenic mechanisms of mtDNA mutations are poorly understood partly due to the striking phenotypic heterogeneity and complications of dynamic mutation heteroplasmy, rendering these conditions very difficult to treat.
This project forms an integral part of the recently established MRC Centre of Research Excellence in Mitochondrial Genome Therapeutics (MRC CoRE-MitoGT) established in collaboration with the Lily Foundation and LHON Collective. CoRE-MitoGT is an international consortium ultimately aims to understand how mtDNA mutations cause disease and develop therapies targeting their root causes. The student will join the Horvath Lab (https://www.horvathlab-cam.co.uk/), one of the core laboratories within CoRE-MitoGT, based at the John Van Geest Centre for Brain Repair and the Cambridge Institute for Medical Research, to investigate how different cell types respond to pathogenic mtDNA mutations in primary and iPSC-derived cellular models of patients with mitochondrial diseases. We will identify the mechanisms why certain cells are particularly susceptible for impaired mitochondrial function leading to stroke-like episodes, epilepsy or mitochondrial myopathy.
The project combines in vitro work on primary and iPSC-derived cellular models and in patients with mitochondrial diseases to investigate:
- Cell-type-specific differences in human brain organoids carrying mtDNA mutations: Characterisation of the molecular signature of heteroplasmic m.3243A>G (MELAS) in different neuronal and glia cells in cortical organoids to identify the molecular base of stroke-like episodes using single cell sequencing strategies combined with molecular validation.
- Assess and manipulate heteroplasmy and mitochondrial function: Determine whether novel mtDNA editing pathways can result in significant shift in heteroplasmy and mitochondrial function of most affected cell types.
- Identify new regulators: By understanding key pathways leading to impairment of some specific neuronal or glia cells we will identify novel treatment targets.
- Study molecular biomarkers in patients with mtDNA mutations: We will look for molecular biomarkers in serum of patients form a large cohort of >200 mitochondrial diseases. Validate the strongest candidates in human neuronal models and, in collaboration with partner groups, mammalian systems, prioritising mechanisms with therapeutic potential, druggability and translational relevance.
Findings from these approaches will be integrated with mammalian and single-cell datasets generated by collaborating groups, positioning the mechanisms identified here within a broader multiscale understanding of mtDNA disease.
The project forms part of a major new collaborative research centre on mtDNA disease and gene-modifying therapy, with access to purpose-built disease models and a network of clinicians and researchers across the Cambridge Biomedical Campus and beyond. Hence, the student will join a large and interactive mitochondrial research community with access to state-of-the-art imaging, proteomics and sequencing facilities and an active postgraduate environment. The student can expect to receive technical training in a range of methodologies such as iPSC-derived neuronal culture, quantitative confocal imaging, mitochondrial biochemistry, molecular biology, mtDNA genotyping by ddPCR and sequencing, and pharmacological evaluation of compounds. In addition, CoRE-MitoGT will provide an extensive programme of personal and professional training including ECR-focused events and development opportunities, as well as promoting best-practice to enhance EDI and positive research culture.
References
- Hathazi D, Lyons C, Lagos D, Podmanicky O, Zarate-Mendez M, Nie Y, Müller JS, Allinson KSJ, Naylor H, Lako M, Elsharkawi I, Muffels I, Morava E, Kozicz T, Chinnery P, Lakatos A, Horvath R. Mitochondrial DNA heteroplasmy drives cortical neuronal disturbances in human organoids harbouring the common m.3243A>G mutation. Nat Commun. 2026 Jun 21;17(1):7840.
- Ratnaike T, Paramonov I, Olimpio C, Hoischen A, Beltran S, Matalonga L; Solve-RD Consortium; Horváth R. Mitochondrial DNA disease discovery through evaluation of genotype and phenotype data: The Solve-RD experience. Am J Hum Genet 2025 Apr 23:S0002-9297(25)00144-2.
- Van Haute L, O'Connor E, Diaz H, Munro B, Polavarapu K, Hock DH, Arunachal G, Athanasiou-Fragkouli A, Bardhan M, Barth M, Bonneau D, Brunetti-Pierri N, Cappuccio G, Caruana NJ, Dominik N, Goel H, Helman G, Houlden H, Lenaers G, et al., Procaccio V, Rius R, Rebelo-Guiomar P, Simons C, Vengali S, Zaki MS, Ziegler A, Thorburn DR, Stroud DA, Maroofian R, Christodoulou J, Gustafsson C, Nalini A, Lochmüller H, Minczuk M, Horvath R. TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease Nat Commun 2023;14(1):1009.