Feeding the deoxyribonucleoside salvage pathway to rescue mitochondrial DNA

•Many severe mitochondrial disorders are associated with impaired mitochondrial DNA replication.•Limited nucleotide availability, a pathomechanism involved in many of these disorders, leads to mitochondrial DNA depletion.•Supply of nucleotide precursors has been shown to prevent mitochondrial DNA depletion in vitro.•Precursor availability may also be enhanced by catabolism inhibition.•We propose the administration of deoxyribonucleosides and/or the inhibition of their catabolism as a therapeutic strategy. Mutations in an increasing number of nuclear genes involved in deoxyribonucleotide homeostasis cause disorders associated with somatic mitochondrial DNA (mtDNA) abnormalities. Dysfunction of the products of these genes leads to limited availability of substrates for mtDNA replication and results in mtDNA depletion, multiple deletions or point mutations; mtDNA depletion is the molecular feature linked to greatest clinical severity. In this review, we discuss recent results demonstrating that enhancement of the salvage pathways by increasing the availability of deoxyribonucleosides needed for each specific genetic defect prevents mtDNA depletion. Hence, we propose administration of selected deoxyribonucleosides and/or inhibitors of their catabolism as a pharmacological strategy to treat these diseases.