Study of the effects of potentially beneficial molecules on the mitochondrial dNTP pool in a model of Hepatocerebral Mitochondrial DNA Depletion Syndrome caused by mutations in the MPV17 gene

Mitochondrial DNA Depletion Syndromes (MDS) are genetically heterogeneous diseases characterized by a severe reduction of mitochondrial DNA (mtDNA) copy number in one or more organs and presenting with a wide spectrum of clinical manifestations. A peculiar form of hepatocerebral mtDNA depletion syndrome is caused by mutations in the MPV17 gene, which encodes a protein of 176 amino-acids located in the inner mitochondrial membrane and highly conservated in mouse (MPV17), zebrafish (TRA) and Saccharomyces cerevisie (SYM1). Although it has been demonstrated that lack of Sym1/Mpv17 determines mtDNA instability in human, mouse and yeast, the role of this protein in mtDNA maintenance remains unclear. The nucleotides decrease reported in mitochondria of mice and fibroblasts of MPV17-mutant patients, has established the mitochondrial dNTP insufficiency as the cause of mtDNA depletion in MPV17 deficiency. Recently also in S. cerevisiae we demonstrated that SYM deletion resulted in a general decrease in all four mitochondrial nucleotides, confirming yeast as an excellent model for the study of the molecular mechanisms underlying the pathologies associated with MPV17 mutations. Despite the remarkable advances in the genetic diagnosis of mitochondrial disorders, treatments for these diseases remain symptomatic and do not provides a relevant improvement in life of the subjects affected. Therefore, a stimulating challenge is to find a successful therapy and to this purpose yeast has been proposed as a suitable model to discover new therapies. In our laboratory, screening of 1018 molecules of the Selleck FDA-approved Drug library led to the identification of 13 potentially therapeutic molecules for MPV17-related MDDS because able to rescue the oxidative growth defect and reduce the mtDNA instability of the sym1 mutant strain. Moreover all molecules are able to determine a significant increase in the mitochondrial dNTP pool thus suggesting that supplementation of the culture medium with these molecules could prevente mtDNA instability in yeast cells and that therefore a decresead availability of DNA synthesis precursors could be the cause of the mtDNA depletion in Sym1/Mpv17 deficiency. It is important to underline that all these molecules are FDA-approved so their use could minimize development costs and speed up an eventual administration in humans.