Decoding how pathogenic mtDNA mutations influence innate immunity and susceptibility to infection (360G-Wellcome-334135_Z_25_Z)

Pathogenic mitochondrial DNA (mtDNA) mutations, including those affecting mitochondrial transfer RNAs (tRNAs) and protein-coding genes, are a leading cause of inherited mitochondrial disease. Clinical observations suggest that patients with mtDNA disease are predisposed to recurrent infections and sepsis, but the mechanisms underlying this vulnerability are unknown. While these mutations disrupt oxidative phosphorylation, their impact on innate immunity remains poorly defined. This proposal aims to elucidate how different classes of heteroplasmic mtDNA mutations influence innate immune responses, focusing on macrophage activation, anti-microbial defence and systemic inflammation. Building on my teams recent discovery that the m.5019A>G mutation in the mt-tRNA for alanine (mt-Ta) drives aberrant type I interferon signalling in macrophages and in vivo, we will compare this to the m.5024C>T mutation in mt-Ta and the m.8069G>A mutation in mt-Atp6 to determine whether immune perturbations are mutation-specific or generalisable across mtDNA disease. We will use metabolic and immunological profiling of primary macrophages and mice in vivo to define how mitochondrial mutations shape innate immunity. Additionally, we will assess whether boosting mtDNA levels with a mtDNA polymerase activator can restore respiratory chain function and re-balance immune responses. This work will uncover fundamental mechanisms linking inherited mtDNA mutations to immune dysregulation and infection susceptibility.