Flynn, Robert James; (2025) From Transcriptomics to Functional Examination: An Investigation of Primary Mitochondrial Disease and Secondary Mitochondrial Dysfunction. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Mitochondrial diseases are a heterogeneous and often clinically severe family of conditions. These diseases frequently present in childhood and are associated with a paucity of effective treatments. Mitochondrial dysfunction can be broadly divided into two categories, primary mitochondrial disease (PMD) and secondary mitochondrial dysfunction (SMD). PMD may be defined as being caused by variants affecting genes which are known to encode components of the mitochondrial proteome. Conversely, SMD can be defined as any mitochondrial dysfunction which does not fall under the umbrella of PMD. Due to recent advancements in sequencing technologies, the list of genes which have been linked to both forms of mitochondrial dysfunction is rapidly expanding. This thesis aims to tackle this challenge by first investigating the mechanisms underpinning PMD. To do so, I have leveraged a large bulk transcriptomic dataset generated using primary dermal fibroblasts derived from a diverse cohort of patients with PMD. Transcriptomics has generated significant advancements in the field of mitochondrial disease in recent years, in particular via identifying pathogenic variants in patients for whom exome sequencing proved insufficient. The second broad aim of this project was to functionally validate novel SMD candidate genes identified via the 100,000 genomes project. With the help of our industry partner, Nanna Therapeutics, I have used dermal fibroblasts derived from these patients to examine numerous facets of mitochondrial function. These assays were then followed by pharmacological rescue experiments aimed at ameliorating the observed mitochondrial phenotype. Together these experiments revealed a complex pattern of transcriptomic alterations in the PMD cohort while also providing striking evidence of altered mitochondrial function associated with the aforementioned candidate genes. These findings highlight several potentially fruitful avenues for future research into both PMD and SMD.

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