AAV-mediated Liver-specific MPV17 Expression Restores mtDNA Levels and Prevents Diet-induced Liver Failure

• DOI: 10.1038/mt.2013.230
• Publication Date: 2013-11-19T13:18:57Z
• Authors: Emanuela Bottani; Carla Giordano; Gabriele Civiletto; Ivano Di Meo; Alberto Auricchio; Emilio Ciusani; Silvia Marchet; Costanza Lamperti; Giulia d'Amati; Carlo Viscomi; Massimo Zeviani
• Keywords: Liver Cirrhosis; Genotype; Genetic Vectors; Gene Expression; DNA, Mitochondrial; Cell Line; Mitochondrial Proteins; Mice; 03 medical and health sciences; Drug Discovery; Genetics; Animals; Humans; Molecular Biology; Pharmacology; Mice, Knockout; 0303 health sciences; Membrane Proteins; Genetic Therapy; Dependovirus; 3. Good health; Molecular Weight; Animals; Cell Line; Dependovirus; Diet, Ketogenic; Disease Models, Animal; Gene Expression; Genetic Therapy; Genetic Vectors; Genotype; Humans; Liver Cirrhosis; Liver Failure; Membrane Proteins; Mice; Mice, Knockout; Mitochondrial Proteins; Molecular Weight; Phenotype; Protein Multimerization; DNA, Mitochondrial; Disease Models, Animal; Phenotype; Molecular Medicine; Protein Multimerization; Diet, Ketogenic; Liver Failure

Mutations in human MPV17 cause a hepatocerebral form of mitochondrial DNA depletion syndrome (MDS) hallmarked by early-onset liver failure, leading to premature death. Liver transplantation and frequent feeding using slow-release carbohydrates are the only available therapies, although surviving patients eventually develop slowly progressive peripheral central neuropathy. The physiological role Mpv17, including its functional link (mtDNA) maintenance, is still unclear. We show here that Mpv17 part high molecular weight complex unknown composition, which essential for mtDNA maintenance critical tissues, i.e. liver, knockout mouse model. On standard diet, Mpv17-/- shows hardly any symptom dysfunction, but ketogenic diet (KD) leads these animals cirrhosis failure. However, when expression carried out adeno-associated virus (AAV)-mediated gene replacement, mice able reconstitute Mpv17-containing supramolecular complex, restore copy number oxidative phosphorylation (OXPHOS) proficiency, prevent failure induced KD. These results open new therapeutic perspectives treatment MPV17-related liver-specific MDS.