A yeast-based repurposing approach revealed modulation of dNTP pool as a therapeutic target to treat mitochondrial DNA depletion syndromes

Mitochondrial DNA Depletion Syndromes (MDS) are a group of clinically heterogenous and often severe diseases characterized by a reduction of the mitochondrial DNA (mtDNA) copy number in affected tissues. There are still no satisfactory therapies and, since mitochondrial diseases, taken individually, are rare, therapeutic strategies with potential general applicability to several mitochondrial diseases would be desirable. Yeast has proved to be an excellent model for the study of the mechanisms underlying mitochondrial pathologies and also for the discovery of new therapies thanks to the development of a high–throughput yeast-based assay. We identified ten drugs active against MPV17 disorder modelled in yeast, whose homologous gene is SYM1. MPV17/SYM1 encodes a non-selective channel in the inner mitochondrial membrane whose physiological role and nature of the cargo remains elusive. Recessive mutations in this gene cause a hepatocerebral form of MDS and Navajo neurohepatopathy. All the ten molecules identified determine a concomitant increase of both mitochondrial dNTP pool and mtDNA stability strongly suggesting that the reduced availability of DNA synthesis precursors is the cause of the mtDNA deletion/depletion in Sym1 deficiency. We also assessed the effect of these molecules on mtDNA stability of two additional MDS yeast models characterized by mutations in MIP1 and RNR2, orthologs of the human genes POLG and RRM2B, respectively, extending the potential use of these drugs to other MDS patients. As a drug repurposing approach of FDA-approved drugs was used, this could speed up a possible clinical use of the drugs.