Dissecting the nuclear supervision of mitochondrial DNA transmission and function (360G-Wellcome-337918_Z_25_Z)

Eukaryotic cells rely on multiple copies of mitochondrial DNA (mtDNA) to support essential cellular activities. During development and ageing, mutations can arise in some mtDNA copies, resulting in heteroplasmy – a mixture of functional and mutant mtDNA that compete for dominance within cells and tissues. When the mutant mtDNA surpasses a critical threshold, it can trigger mitochondrial diseases and age-related conditions. The nuclear genome, which encodes most of the mitochondrial proteome and all external regulators of mitochondrial biogenesis and activities, shapes these heteroplasmy dynamics. Yet, the mechanisms remain poorly understood. When a mtDNA variant reaches 100% (homoplasmy), nuclear variations can further modulate its pathogenicity through mito-nuclear interactions. To date, progress in resolving these interactions has been hindered by the lack of genetic tools and model systems. This research aims to transform our understanding of how mtDNA mutation burden and function are regulated. Leveraging innovative mtDNA toolkits and high-throughput genetic and small-molecule screens we developed in Drosophila, this work will uncover and characterise the nuclear-encoded proteins that 1) modulate mtDNA heteroplasmy levels, and 2) mitigate the defects of harmful homoplasmic mutations. It will provide transformative insights into genome maintenance, ageing, and evolution, paving the way for novel strategies to treat mtDNA-linked diseases.