title: Early-onset liver mtDNA depletion and late-onset proteinuric nephropathy in Mpv17 knockout mice.
abstract: In humans, MPV17 mutations are responsible for severe mitochondrial depletion syndrome, mainly affecting the liver and the nervous system. To gain insight into physiopathology of MPV17-related disease, we investigated an available Mpv17 knockout animal model. We found severe mtDNA depletion in liver and, albeit to a lesser extent, in skeletal muscle, whereas hardly any depletion was detected in brain and kidney, up to 1 year after birth. Mouse embryonic fibroblasts did show mtDNA depletion, but only after several culturing passages, or in a serumless culturing medium. In spite of severe mtDNA depletion, only moderate decrease in respiratory chain enzymatic activities, and mild cytoarchitectural alterations, were observed in the Mpv17(-/-) livers, but neither cirrhosis nor failure ever occurred in this organ at any age. The mtDNA transcription rate was markedly increased in liver, which could contribute to compensate the severe mtDNA depletion. This phenomenon was associated with specific downregulation of Mterf1, a negative modulator of mtDNA transcription. The most relevant clinical features involved skin, inner ear and kidney. The coat of the Mpv17(-/-) mice turned gray early in adulthood, and 18-month or older mice developed focal segmental glomerulosclerosis (FSGS) with massive proteinuria. Concomitant degeneration of cochlear sensory epithelia was reported as well. These symptoms were associated with significantly shorter lifespan. Coincidental with the onset of FSGS, there was hardly any mtDNA left in the glomerular tufts. These results demonstrate that Mpv17 controls mtDNA copy number by a highly tissue- and possibly cytotype-specific mechanism.
authors.affiliation: Unit of Molecular Neurogenetics - Pierfranco and Luisa Mariani Center for the Study of Mitochondrial Disorders in Children, IRCCS Foundation Neurological Institute C. Besta, Milan, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Viscomi
authors.forename: Antonella
authors.initials: A
authors.lastname: Spinazzola
authors.forename: Marco
authors.initials: M
authors.lastname: Maggioni
authors.forename: Erika
authors.initials: E
authors.lastname: Fernandez-Vizarra
authors.forename: Valeria
authors.initials: V
authors.lastname: Massa
authors.forename: Claudio
authors.initials: C
authors.lastname: Pagano
authors.forename: Roberto
authors.initials: R
authors.lastname: Vettor
authors.forename: Marina
authors.initials: M
authors.lastname: Mora
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
mesh_terms: D017668:Age of Onset; D000818:Animals; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism; D005923:Glomerulosclerosis, Focal Segmental / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity; D011507:Proteinuria / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D004272:DNA, Mitochondrial; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C065292:Mpv17 protein, mouse; D014157:Transcription Factors; C495174:mTERF protein, mouse