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Early-onset liver mtDNA depletion and late-onset proteinuric nephropathy in Mpv17 knockout mice. Hum Mol Genet

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.
Human Molecular Genetics (Impact Factor: 6.68). 10/2008; 18(1):12-26. DOI: 10.1093/hmg/ddn309
Source: PubMed

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.

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    • "), and genes with poorly defined functions related to mtDNA maintenance, including, MPV17 and, interestingly, subunits of the Kreb's cycle enzyme Succinyl-CoA Synthetase, SCS (SUCLG1, SUCLA2) (Suomalainen and Isohanni, 2010). While animal models have been reported for many of these genes (Haraguchi et al., 2002; Kimura et al., 2003; Hance et al., 2005; Tyynismaa et al., 2005; Akman et al., 2008; Martinez-Azorin et al., 2008; Lopez et al., 2009; Viscomi et al., 2009), there is currently no reported animal model for SCS–dependent mtDNA depletion. SCS is the TCA cycle enzyme responsible for the conversion of succinyl-CoA to succinate in the mitochondrial matrix that is coupled to the phosphorylation of GDP or ADP, thereby providing the only " substrate level " phosphorylation in the TCA cycle. "
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    • "Induction prevents cardiovascular injury via anti-inflammatory effects [37], protects against platelet aggregation, and limits growth of vascular smooth muscle cells [38], effects that could contribute to I-R resistance in vivo. The function of induced Mpv17 is poorly understood, though there is evidence this inner mitochondrial membrane protein may regulate mtDNA copy number and longevity [39]. Tfrc encodes the transferrin receptor, which contributes to iron handling and could facilitate iron-dependent oxidative stress. "
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