Mitochondrial DNA (mtDNA) is essential for energy production and mutations in this molecule cause an energy crisis, with consequent disease. Hence, we demonstrate that mitochondrial fitness dictates metabolite preference for mtDNA replication consequently, interventions that restrict metabolite availability can suppress pathological mtDNAs, by coupling mitochondrial fitness and replication. Additionally, by restricting glucose utilization, 2DG supports functional mtDNAs, as glucose-fuelled respiration is critical for mtDNA replication in control cells, when glucose and glutamine are scarce. Mechanistically, 2DG selectively inhibits the replication of mutant mtDNA and glutamine is the key target metabolite, as its withdrawal, too, suppresses mtDNA synthesis in mutant cells. Here, we show that both compounds selected wild-type over mutant mtDNA, restoring mtDNA expression and respiration. Glucose and glutamine consumption are increased in mtDNA dysfunction, and so we targeted the use of both in cells carrying the pathogenic m.3243A>G variant with 2-Deoxy-D-glucose (2DG), or the related 5-thioglucose. Because mitochondrial fitness does not favour the propagation of functional mtDNAs in disease states, we sought to create conditions where it would be advantageous. Pathological variants of human mitochondrial DNA (mtDNA) typically co-exist with wild-type molecules, but the factors driving the selection of each are not understood.
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