Understanding of the Mitochondrial DNA Depletion Syndrome (MDDS) caused by rare mutations in the Mpv17 gene and possible therapeutic approaches.
MDMD (Mitochondrial DNA Maintenance Disease) describes a group of rare, very severe, mostly lethal, genetic diseases. Mitochondrial DNA Depletion Syndrome(MDDS) is a subclass of these genetic diseases characterised by serious, mostly lethal, infantile liver disease and neuropathy. Mpv17 is one of the genes, in which mutations cause gene cause such conditions. Mutations in the evolutionary conserved Mpv17 homologs in other species cause different but not obviously related phenotypes in mice, zebra fish and yeast, whereby the human gene can complement the defect in mice and yeast, for example.
The mechanism causing the pathology appears to involve a lack of nucleotides as mitochondrial DNA precursors, but the molecular mechanism leading to this condition remains elusive.
While it is clear that the Mpv17 protein is an organellar membrane protein, the literature is controversial as far as its localization is concerned. Some scientists believe the protein to localize to the mitochondrial inner membrane, while our data contradicts this view placing the protein in other intracellular organells. In the first case, in Mpv17 mutants, the import of nucleotide precursors into mitochondria would be directly impaired, while we think that a salvage pathway retrieving used nucleotide precursors into the cytoplasm is affected. Consistently, in our view, it would be beneficial for the patient to keep the level of nucleotide precursors high in the cytoplasm offering an entry site for such therapeutic intervention. This hypothesis offers a starting point for future research on the delivery of nucleotides and their derivatives into the MDDS depleted cell.