Administration of deoxyribonucleosides or inhibition of their catabolism as a pharmacological approach for mitochondrial DNA depletion syndrome

Abstract

Mitochondrial DNA (mtDNA) depletion syndrome (MDS) is characterized by a reduction in mtDNA copy number and consequent mitochondrial dysfunction in affected tissues. A subgroup of MDS is caused by mutations in genes that disrupt deoxyribonucleotide metabolism, which ultimately leads to limited availability of one or several deoxyribonucleoside triphosphates (dNTPs), and subsequent mtDNA depletion. Here, using in vitro experimental approaches (primary cell culture of deoxyguanosine kinase-deficient cells and thymidine-induced mtDNA depletion in culture as a model of mitochondrial neurogastrointestinal encephalomyopathy, MNGIE), we show that supplements of those deoxyribonucleosides (dNs) involved in each biochemical defect (deoxyguanosine or deoxycytidine, dCtd) prevents mtDNA copy number reduction. Similar effects can be obtained by specific inhibition of dN catabolism using tetrahydrouridine (THU; inhibitor of cytidine deaminase) or immucillin H (inhibitor of purine nucleoside phosphorylase). In addition, using an MNGIE animal model, we provide evidence that mitochondrial dNTP content can be modulated in vivo by systemic administration of dCtd or THU. In spite of the severity associated with diseases due to defects in mtDNA replication, there are currently no effective therapeutic options available. Only in the case of MNGIE, allogeneic hematopoietic stem cell transplantation has proven efficient as a long-term therapeutic strategy. We propose increasing cellular availability of the deficient dNTP precursor by direct administration of the dN or inhibition of its catabolism, as a potential treatment for mtDNA depletion syndrome caused by defects in dNTP metabolism.

How do changes in the mtDNA and mitochondrial dysfunction influence cancer and cancer therapy? Challenges, opportunities and models

“…Murine UPP-1, unlike human UPP-1, cleaves thymidine as well as uridine; therefore, the full capacity to cleave mouse thymidine is abolished in this mouse model [221][222][223]. In addition, deficiencies of complex I and IV could be observed in the brain of very old Tp À/À Upp-1 À/À mice [223].…”

Emerging therapies for mitochondrial diseases

“…Depletion of mtDNA has been corrected in vivo in a TppUpp double knockout mouse model of MNGIE disease by administrating deoxycytidine or tetrahydrouridine (77). In the same study, the addition of deoxycytidine and tetrahydrouridine to a cell model of MNGIE disease (dThd-induced mtDNA depleted fibroblasts) was also able to prevent mtDNA depletion.…”

“…In the same study, the addition of deoxycytidine and tetrahydrouridine to a cell model of MNGIE disease (dThd-induced mtDNA depleted fibroblasts) was also able to prevent mtDNA depletion. Depletion of mtDNA was also corrected in dGK deficient human fibroblasts by adding deoxyguanosine (77). …”

Recognition, investigation and management of mitochondrial disease

“…Other novel therapeutic approaches include targeting the mitochondrial membrane and its complex lipids46; replacing nucleosides in mtDNA depletion disorders that are associated with nucleoside deficiency47; and gene therapy approaches including recoding mtDNA-encoded genes to be expressed in the nuclear genome (allotopic gene expression), ‘conventional’ viral vector-mediated nuclear-targeted gene therapies; and selective destruction of mutant mtDNA using restriction endonuclease technologies (see ref 5). …”