Rewiring cell signalling pathways in pathogenic mtDNA mutations

Mitochondria generate the energy to sustain cell viability and serve as a hub for cell signalling. Their own genome (mtDNA) encodes genes critical for oxidative phosphorylation. Mutations of mtDNA cause major disease and disability with a wide range of presentations and severity. We review here an emerging body of data suggesting that changes in cell metabolism and signalling pathways in response to the presence of mtDNA mutations play a key role in shaping disease presentation and progression. Understanding the impact of mtDNA mutations on cellular energy homeostasis and signalling pathways seems fundamental to identify novel therapeutic interventions with the potential to improve the prognosis for patients with primary mitochondrial disease. Mutations of mitochondrial DNA (mtDNA) cause disease with a wide range of presentations and severity. The relationships between genotype and phenotype are not understood.Mitochondrial heteroplasmy is the presence of more than one type of mitochondrial DNA within cells and tissues: notably mtDNA with a mutation and wild-type mtDNA.Disease severity broadly correlates with the burden of mutant mtDNA (mutant load). A biochemical ‘threshold effect’ dictates that people with lower mutant burden may even be asymptomatic.Individual mtDNA mutations lead to distinct metabolic remodelling associated with or driven by alterations in cell signalling pathways.Understanding the interactions between mtDNA mutations, cell signalling pathways and energy homeostasis opens new horizons for potential therapeutic interventions to improve the outlook for patients with these diseases.