MPV17 explained

Protein MPV17 is a protein that in humans is encoded by the MPV17 gene.[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]

Function

This protein was first thought to be a peroxisomal protein, but in 2006, Spinazzola et al. demonstrated that it is a mitochondrial inner membrane protein that is implicated in the formation of reactive oxygen species (ROS).[2]

Restoration of Mpv17 expression in Mpv17-/- mice restores 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]

Structure

Gene

The human MPV17 gene is located on chromosome 2 at p21-23, comprising eight exons encoding 176 amino acids.[3]

Protein

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. 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.

Interactions

MPV17 has been shown to interact with Prkdc protein during Adriamycin-induced nephropathy in mice.[10]

See also

Further reading

Notes and References

  1. Karasawa M, Zwacka RM, Reuter A, Fink T, Hsieh CL, Lichter P, Francke U, Weiher H . The human homolog of the glomerulosclerosis gene Mpv17: structure and genomic organization . Human Molecular Genetics . 2 . 11 . 1829–34 . Nov 1993 . 8281143 . 10.1093/hmg/2.11.1829 .
  2. Spinazzola 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 . MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion . Nature Genetics . 38 . 5 . 570–5 . May 2006 . 16582910 . 10.1038/ng1765 . 11577/3321860 . 17999433 . free .
  3. Web site: Entrez Gene: MPV17 MpV17 mitochondrial inner membrane protein.
  4. Uusimaa J, Evans J, Smith C, Butterworth A, Craig K, Ashley N, Liao C, Carver J, Diot A, Macleod L, Hargreaves I, Al-Hussaini A, Faqeih E, Asery A, Al Balwi M, Eyaid W, Al-Sunaid A, Kelly D, van Mourik I, Ball S, Jarvis J, Mulay A, Hadzic N, Samyn M, Baker A, Rahman S, Stewart H, Morris AA, Seller A, Fratter C, Taylor RW, Poulton J . Clinical, biochemical, cellular and molecular characterization of mitochondrial DNA depletion syndrome due to novel mutations in the MPV17 gene . European Journal of Human Genetics . 22 . 2 . 184–91 . Feb 2014 . 23714749 . 10.1038/ejhg.2013.112 . 3895632.
  5. Viscomi C, Spinazzola A, Maggioni M, Fernandez-Vizarra E, Massa V, Pagano C, Vettor R, Mora M, Zeviani M . Early-onset liver mtDNA depletion and late-onset proteinuric nephropathy in Mpv17 knockout mice . Human Molecular Genetics . 18 . 1 . 12–26 . Jan 2009 . 18818194 . 10.1093/hmg/ddn309 . 2644642.
  6. Bottani E, Giordano C, Civiletto G, Di Meo I, Auricchio A, Ciusani E, Marchet S, Lamperti C, d'Amati G, Viscomi C, Zeviani M . AAV-mediated liver-specific MPV17 expression restores mtDNA levels and prevents diet-induced liver failure . Molecular Therapy . 22 . 1 . 10–7 . Jan 2014 . 24247928 . 3880585 . 10.1038/mt.2013.230 .
  7. Casalena G, Krick S, Daehn I, Yu L, Ju W, Shi S, Tsai SY, D'Agati V, Lindenmeyer M, Cohen CD, Schlondorff D, Bottinger EP . Mpv17 in mitochondria protects podocytes against mitochondrial dysfunction and apoptosis in vivo and in vitro . American Journal of Physiology. Renal Physiology . 306 . 11 . F1372-80 . Jun 2014 . 24598802 . 10.1152/ajprenal.00608.2013 . 4042102.
  8. Antonenkov VD, Isomursu A, Mennerich D, Vapola MH, Weiher H, Kietzmann T, Hiltunen JK . The Human Mitochondrial DNA Depletion Syndrome Gene MPV17 Encodes a Non-selective Channel That Modulates Membrane Potential . The Journal of Biological Chemistry . 290 . 22 . 13840–61 . May 2015 . 25861990 . 10.1074/jbc.M114.608083 . 4447960. free .
  9. Blakely EL, Butterworth A, Hadden RD, Bodi I, He L, McFarland R, Taylor RW . MPV17 mutation causes neuropathy and leukoencephalopathy with multiple mtDNA deletions in muscle . Neuromuscular Disorders . 22 . 7 . 587–91 . Jul 2012 . 22508010 . 10.1016/j.nmd.2012.03.006 . 3387382.
  10. Papeta N, Zheng Z, Schon EA, Brosel S, Altintas MM, Nasr SH, Reiser J, D'Agati VD, Gharavi AG . Prkdc participates in mitochondrial genome maintenance and prevents Adriamycin-induced nephropathy in mice . The Journal of Clinical Investigation . 120 . 11 . 4055–64 . Nov 2010 . 20978358 . 10.1172/JCI43721 . 2964992.

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