Research of potentially therapeutic molecules for Hepatocerebral Mitochondrial DNA Depletion Syndrome caused by mutations in the MPV17 gene

Mitochondrial DNA depletion syndromes (MDDS) are autosomal recessive disorders characterized by severe reduction in mitochondrial DNA (mtDNA) copy number in one or several tissues, leading to impaired energy production in affected tissues and organs. A peculiar form of hepatocerebral mtDNA depletion syndrome is caused by mutations in the MPV17 gene, which encodes a small hydrophobic protein located in the mitochondrial inner membrane. Thanks to the high degree of conservation observed between MPV17 and its yeast homolog SYM1, it was possible to elucidate the molecular consequences of MPV17 variants identified in MDDS patients. It was demonstrated that Sym1 takes part in a high molecular weight complex to form a membrane pore capable of allowing the transport of large molecules, such as metabolites, across the inner mitochondrial membrane. However, the specific role of the complex and the nature of molecules transported by the Sym1-Mpv17 channel remain elusive. More recently it has been observed, in mouse and patient-derived cells characterized by MPV17 deficiency, a decrease in the mitochondrial dNTPs pool suggesting that loss of function of Mpv17 causes nucleotide insufficiency in the mitochondria that slows rate of mtDNA replication and induce mtDNA depletion. So it has been suggested that Mpv17 forms a channel in the inner mitochondrial membrane, supplying the matrix with deoxynucleotide phosphates and/or nucleotide precursors