title: Abolition of peroxiredoxin-5 mitochondrial targeting during canid evolution.
abstract: In human, the subcellular targeting of peroxiredoxin-5 (PRDX5), a thioredoxin peroxidase, is dependent on the use of multiple alternative transcription start sites and two alternative in-frame translation initiation sites, which determine whether or not the region encoding a mitochondrial targeting sequence (MTS) is translated. In the present study, the abolition of PRDX5 mitochondrial targeting in dog is highlighted and the molecular mechanism underlying the loss of mitochondrial PRDX5 during evolution is examined. Here, we show that the absence of mitochondrial PRDX5 is generalized among the extant canids and that the first events leading to PRDX5 MTS abolition in canids involve a mutation in the more 5' translation initiation codon as well as the appearance of a STOP codon. Furthermore, we found that PRDX5 MTS functionality is maintained in giant panda and northern elephant seal, which are phylogenetically closely related to canids. Also, the functional consequences of the restoration of mitochondrial PRDX5 in dog Madin-Darby canine kidney (MDCK) cells were investigated. The restoration of PRDX5 mitochondrial targeting in MDCK cells, instead of protecting, provokes deleterious effects following peroxide exposure independently of its peroxidase activity, indicating that mitochondrial PRDX5 gains cytotoxic properties under acute oxidative stress in MDCK cells. Altogether our results show that, although mitochondrial PRDX5 cytoprotective function against oxidative stress has been clearly demonstrated in human and rodents, PRDX5 targeting to mitochondria has been evolutionary lost in canids. Moreover, restoration of mitochondrial PRDX5 in dog MDCK cells, instead of conferring protection against peroxide exposure, makes them more vulnerable.
authors.affiliation: Institut des Sciences de la Vie, Université catholique de Louvain, Louvain-la-Neuve, Belgium.
authors.forename: Valérie
authors.initials: V
authors.lastname: Van der Eecken
authors.forename: André
authors.initials: A
authors.lastname: Clippe
authors.forename: Sophie
authors.initials: S
authors.lastname: Dekoninck
authors.forename: Julie
authors.initials: J
authors.lastname: Goemaere
authors.forename: Geoffroy
authors.initials: G
authors.lastname: Walbrecq
authors.forename: Paul P
authors.initials: PP
authors.lastname: Van Veldhoven
authors.forename: Bernard
authors.initials: B
authors.lastname: Knoops
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004285:Dogs; D006801:Humans; D008969:Molecular Sequence Data; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D054464:Peroxiredoxins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: C515974:PRDX5 protein, human; D054464:Peroxiredoxins
references.citation: FEBS Lett. 2003 Jun 5;544(1-3):148-52
references.pmid: 12782306
references.citation: Cell. 2008 Jul 11;134(1):112-23
references.pmid: 18614015
references.citation: J Pharmacol Toxicol Methods. 2012 Sep;66(2):135-44
references.pmid: 22445855
references.citation: Antioxid Redox Signal. 2011 Aug 1;15(3):817-29
references.pmid: 20977338
references.citation: Free Radic Biol Med. 2004 Jan 1;36(1):65-77
references.pmid: 14732291
references.citation: J Biol Chem. 1984 Jul 25;259(14):9064-75
references.pmid: 6746639
references.citation: Curr Biol. 2010 Nov 9;20(21):R915-9
references.pmid: 21056828
references.citation: J Peripher Nerv Syst. 2006 Dec;11(4):318-24
references.pmid: 17117940
references.citation: FEBS Lett. 1996 Jun 10;388(1):80-4
references.pmid: 8654595
references.citation: J Biol Chem. 2000 Jul 7;275(27):20346-54
references.pmid: 10751410
references.citation: Eur J Biochem. 1996 Nov 1;241(3):779-86
references.pmid: 8944766
references.citation: Biochimie. 2011 Feb;93(2):306-13
references.pmid: 20937353
references.citation: Free Radic Biol Med. 2001 Feb 15;30(4):412-24
references.pmid: 11182297
references.citation: Bioinformatics. 2007 Nov 1;23(21):2947-8
references.pmid: 17846036
references.citation: Mitochondrion. 2011 Nov;11(6):973-81
references.pmid: 21763786
references.citation: J Biol Chem. 1999 Oct 22;274(43):30451-8
references.pmid: 10521424
references.citation: J Mol Biol. 2000 Jul 21;300(4):1005-16
references.pmid: 10891285
references.citation: DNA Seq. 2007 Oct;18(5):380-4
references.pmid: 17654014
references.citation: Arch Biochem Biophys. 2007 Nov 1;467(1):95-106
references.pmid: 17892856
references.citation: Biochim Biophys Acta. 2007 Jul-Aug;1769(7-8):472-83
references.pmid: 17628720
references.citation: Genome Res. 2005 Dec;15(12):1706-16
references.pmid: 16339369
references.citation: Comp Biochem Physiol A Mol Integr Physiol. 2012 Aug;162(4):323-30
references.pmid: 22507522
references.citation: Eur J Biochem. 1999 Mar;260(2):336-46
references.pmid: 10095767
references.citation: Protein Sci. 2005 Oct;14(10):2610-21
references.pmid: 16195549
references.citation: J Mol Biol. 2004 Jul 16;340(4):819-27
references.pmid: 15223323
references.citation: Mol Biol Evol. 2004 Apr;21(4):632-46
references.pmid: 14739251
references.citation: Neurosci Lett. 2008 Mar 15;433(3):219-24
references.pmid: 18262354
references.citation: Nature. 2005 Dec 8;438(7069):803-19
references.pmid: 16341006
references.citation: FEBS Lett. 2005 Apr 25;579(11):2327-33
references.pmid: 15848167
references.citation: Protein Eng. 1997 Jan;10(1):1-6
references.pmid: 9051728
references.citation: Biochem J. 2009 Apr 15;419(2):437-45
references.pmid: 19128239
references.citation: Invest Ophthalmol Vis Sci. 2004 Jan;45(1):23-9
references.pmid: 14691149
references.citation: Free Radic Biol Med. 2003 Apr 1;34(7):862-72
references.pmid: 12654475
references.citation: Mol Biol Evol. 2000 Mar;17(3):387-400
references.pmid: 10723739
references.citation: Antioxid Redox Signal. 2011 Aug 1;15(3):781-94
references.pmid: 20919930
references.citation: FEBS Lett. 2004 Jul 30;571(1-3):161-5
references.pmid: 15280035
references.citation: Fish Shellfish Immunol. 2011 Jan;30(1):309-16
references.pmid: 21078396
references.citation: Arch Biochem Biophys. 2008 Sep 1;477(1):98-104
references.pmid: 18489898
references.citation: Mol Reprod Dev. 2004 Nov;69(3):243-51
references.pmid: 15349835
references.citation: Biochem Biophys Res Commun. 2001 Jun 15;284(3):667-73
references.pmid: 11396953
references.citation: Biochem Biophys Res Commun. 2000 Feb 24;268(3):921-7
references.pmid: 10679306
references.citation: J Biol Chem. 1999 Oct 15;274(42):29897-904
references.pmid: 10514471