Human Molecular Genetics Advance Access first published online on September 24, 2008
This version published online on September 29, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn309
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Early-onset liver mtDNA depletion and late-onset proteinuric nephropathy in Mpv17 knockout mice
1 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 2 Service of Pathology, San Paolo University Hospital, Milan, Italy 3 Department of Medical and Surgical Sciences, University of Padova School of Medicine, Padova, Italy 4 Unit of Neuromuscular Diseases, IRCCS Foundation Neurological Institute "C. Besta", Milan, Italy
Correspondence to: Massimo Zeviani Unit of Molecular Neurogenetics IRCCS Foundation Neurological Institute "C. Besta" Via Temolo, 4 20126 Milan, Italy Phone +390223942630 Fax +390223942619 e-mail zeviani{at}istituto-besta.it
Received August 2, 2008; Revised September 22, 2008; Accepted September 22, 2008
In humans, MPV17 mutations are responsible of severe mitochondrial depletion syndrome, mainly affecting the liver and the nervous system. To gain insight on the 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 one year after birth. Mouse embryonic fibroblasts did show mtDNA depletion, but only after several culturing passages, or in a serum-less culturing medium. In spite of severe mtDNA depletion, only moderate decrease of 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 grey early in adulthood, and 18 month- or older animals 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.
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