Protein MPV17 is a protein that in humans is encoded by the MPV17gene.[1][2][3] It is a mitochondrial inner membrane protein, which has a so far largely unknown role in mtDNA maintenance. Protein MPV17 is expressed in human pancreas, kidney, muscle, liver, lung, placenta, brain and heart.[4] Human MPV17 is the orthologue of the mouse kidney disease gene, Mpv17. Loss of function has been shown to cause hepatocerebral mtDNA depletion syndromes (MDS) with oxidative phosphorylation failure and mtDNA depletion both in affected individuals and in Mpv17−/− mice.[2][5]
This protein was first thought to be a peroxisomal protein, but in 2006, Spinazzola demonstrated that it is a mitochondrial inner membrane protein that is implicated in the formation of reactive oxygen species (ROS).
Restoration of Mpv17 expression in a Mpv17-/- mice restore mtDNA copy number, suggesting MPV17 is involved in mtDNA copy number, and in mtDNA maintenance.[6]
MPV17 seems to be also involved in apoptosis in podocytes, and involved in ROS.[7]
MPV17 belongs to a family of integral membrane proteins consisting of four members (PXMP2, MPV17, MP-L, and FKSG24 (MPV17L2)) in mammals and two members (Sym1 and Yor292) in yeast. The amino acid sequence of MPV17 (176 amino acids) contains four cysteine residues and three putative phosphorylation sites implies that this protein may act as a redox- and ATP-sensitive channel.[8]
Clinical significance
Mutations in this gene have been associated with the hepatocerebral form of mitochondrial DNA depletion syndrome (MDS), a mutation in this protein leads to an mtDNA (mitochondrial DNA) copy number decrease.[3] By 2013, MDS caused by MPV17 mutations had been reported in 32 patients with the clinical manifestations including early progressive liver failure, neurological abnormalities, hypoglycaemia and raised blood lactate.[4] In addition, MPV17 mutations have also been associated with autosomal recessive adult-onset neuropathy and leukoencephalopathy with multiple mtDNA deletions in skeletal muscle.[9] Thus, MPV17 mutations can lead to recessive MDS or recessive multiple mtDNA deletion disorders.
↑Karasawa M, Zwacka RM, Reuter A, Fink T, Hsieh CL, Lichter P, Francke U, Weiher H (Nov 1993). "The human homolog of the glomerulosclerosis gene Mpv17: structure and genomic organization". Human Molecular Genetics. 2 (11): 1829–34. doi:10.1093/hmg/2.11.1829. PMID8281143.
↑ 2.02.1Spinazzola A, Viscomi C, Fernandez-Vizarra E, Carrara F, D'Adamo P, Calvo S, Marsano RM, Donnini C, Weiher H, Strisciuglio P, Parini R, Sarzi E, Chan A, DiMauro S, Rötig A, Gasparini P, Ferrero I, Mootha VK, Tiranti V, Zeviani M (May 2006). "MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion". Nature Genetics. 38 (5): 570–5. doi:10.1038/ng1765. PMID16582910.
Schenkel J, Zwacka RM, Rutenberg C, Reuter A, Waldherr R, Weiher H (Jul 1995). "Functional rescue of the glomerulosclerosis phenotype in Mpv17 mice by transgenesis with the human Mpv17 homologue". Kidney International. 48 (1): 80–4. doi:10.1038/ki.1995.270. PMID7564095.
Weiher H (1993). "Glomerular sclerosis in transgenic mice: the Mpv-17 gene and its human homologue". Advances in Nephrology From the Necker Hospital. 22: 37–42. PMID8427063.
Iida R, Yasuda T, Tsubota E, Takatsuka H, Masuyama M, Matsuki T, Kishi K (Feb 2003). "M-LP, Mpv17-like protein, has a peroxisomal membrane targeting signal comprising a transmembrane domain and a positively charged loop and up-regulates expression of the manganese superoxide dismutase gene". The Journal of Biological Chemistry. 278 (8): 6301–6. doi:10.1074/jbc.M210886200. PMID12471025.
Calvo S, Jain M, Xie X, Sheth SA, Chang B, Goldberger OA, Spinazzola A, Zeviani M, Carr SA, Mootha VK (May 2006). "Systematic identification of human mitochondrial disease genes through integrative genomics". Nature Genetics. 38 (5): 576–82. doi:10.1038/ng1776. PMID16582907.
Iida R, Yasuda T, Tsubota E, Takatsuka H, Matsuki T, Kishi K (Jun 2006). "Human Mpv17-like protein is localized in peroxisomes and regulates expression of antioxidant enzymes". Biochemical and Biophysical Research Communications. 344 (3): 948–54. doi:10.1016/j.bbrc.2006.04.008. PMID16631601.
Wong LJ, Brunetti-Pierri N, Zhang Q, Yazigi N, Bove KE, Dahms BB, Puchowicz MA, Gonzalez-Gomez I, Schmitt ES, Truong CK, Hoppel CL, Chou PC, Wang J, Baldwin EE, Adams D, Leslie N, Boles RG, Kerr DS, Craigen WJ (Oct 2007). "Mutations in the MPV17 gene are responsible for rapidly progressive liver failure in infancy". Hepatology. 46 (4): 1218–27. doi:10.1002/hep.21799. PMID17694548.
