title: AAV-mediated liver-specific MPV17 expression restores mtDNA levels and prevents diet-induced liver failure.
abstract: 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.
authors.affiliation: Unit of Molecular Neurogenetics, The Foundation "Carlo Besta" Institute of Neurology IRCCS, Milan, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Bottani
authors.affiliation: Department of Radiological, Oncological, and Pathological Sciences, Sapienza University, Roma, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Giordano
authors.affiliation: Unit of Molecular Neurogenetics, The Foundation "Carlo Besta" Institute of Neurology IRCCS, Milan, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Civiletto
authors.affiliation: Unit of Molecular Neurogenetics, The Foundation "Carlo Besta" Institute of Neurology IRCCS, Milan, Italy.
authors.forename: Ivano
authors.initials: I
authors.lastname: Di Meo
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, Telethon Institute of Genetics and Medicine, "Federico II" University, Naples, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Auricchio
authors.affiliation: Laboratory of Clinical Pathology and Medical Genetics, The Foundation "Carlo Besta" Institute of Neurology IRCCS, Milan, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Ciusani
authors.affiliation: Unit of Molecular Neurogenetics, The Foundation "Carlo Besta" Institute of Neurology IRCCS, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Marchet
authors.affiliation: Unit of Molecular Neurogenetics, The Foundation "Carlo Besta" Institute of Neurology IRCCS, Milan, Italy.
authors.forename: Costanza
authors.initials: C
authors.lastname: Lamperti
authors.affiliation: Department of Radiological, Oncological, and Pathological Sciences, Sapienza University, Roma, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: d'Amati
authors.affiliation: Unit of Molecular Neurogenetics, The Foundation "Carlo Besta" Institute of Neurology IRCCS, Milan, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Viscomi
authors.affiliation: 1] Unit of Molecular Neurogenetics, The Foundation "Carlo Besta" Institute of Neurology IRCCS, Milan, Italy [2] MRC-Mitochondrial Biology Unit, Cambridge, UK.
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
mesh_terms: D000818:Animals; D002460:Cell Line; D004272:DNA, Mitochondrial; D000229:Dependovirus / Q000235:genetics*; D055423:Diet, Ketogenic / Q000009:adverse effects*; D004195:Disease Models, Animal; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology / Q000473:pathology / Q000628:therapy; D017093:Liver Failure / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control / Q000628:therapy*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008970:Molecular Weight; D010641:Phenotype; D055503:Protein Multimerization
chemical_list: D004272:DNA, Mitochondrial; C530370:MPV17 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins