AAV-mediated liver-specific MPV17 expression restores mtDNA levels and prevents diet-induced liver failure.

TitleAAV-mediated liver-specific MPV17 expression restores mtDNA levels and prevents diet-induced liver failure.
Publication TypeJournal Article
Year of Publication2014
AuthorsBottani, E, Giordano, C, Civiletto, G, Di Meo, I, Auricchio, A, Ciusani, E, Marchet, S, Lamperti, C, d'Amati, G, Viscomi, C, Zeviani, M
JournalMol Ther
Date Published2014 Jan
KeywordsAnimals, Cell Line, Dependovirus, Diet, Ketogenic, Disease Models, Animal, DNA, Mitochondrial, Gene Expression, Genetic Therapy, Genetic Vectors, Genotype, Humans, Liver Cirrhosis, Liver Failure, Membrane Proteins, Mice, Mice, Knockout, Mitochondrial Proteins, Molecular Weight, Phenotype, Protein Multimerization

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 and central neuropathy. The physiological role of Mpv17, including its functional link to mitochondrial DNA (mtDNA) maintenance, is still unclear. We show here that Mpv17 is part of a high molecular weight complex of unknown composition, which is essential for mtDNA maintenance in critical tissues, i.e. liver, of a Mpv17 knockout mouse model. On a standard diet, Mpv17-/- mouse shows hardly any symptom of liver dysfunction, but a ketogenic diet (KD) leads these animals to liver cirrhosis and failure. However, when expression of human MPV17 is carried out by adeno-associated virus (AAV)-mediated gene replacement, the Mpv17 knockout mice are able to reconstitute the Mpv17-containing supramolecular complex, restore liver mtDNA copy number and oxidative phosphorylation (OXPHOS) proficiency, and prevent liver failure induced by the KD. These results open new therapeutic perspectives for the treatment of MPV17-related liver-specific MDS.

Alternate JournalMol. Ther.
Citation Key10.1038/mt.2013.230
PubMed ID24247928
PubMed Central IDPMC3880585
Grant ListGGP11011 / / Telethon / Italy
MC_UP_1002/1 / / Medical Research Council / United Kingdom
322424 / / European Research Council / International
TGM11MT6 / / Telethon / Italy
GPP10005 / / Telethon / Italy