title: Mitochondrial p53 mediates a transcription-independent regulation of cell respiration and interacts with the mitochondrial F₁F0-ATP synthase.
abstract: We and others previously reported that endogenous p53 can be located at mitochondria in the absence of stress, suggesting that p53 has a role in the normal physiology of this organelle. The aim of this study was to characterize in unstressed cells the intramitochondrial localization of p53 and identify new partners and functions of p53 in mitochondria. We find that the intramitochondrial pool of p53 is located in the intermembrane space and the matrix. Of note, unstressed HCT116 p53(+/+) cells simultaneously show increased O₂ consumption and decreased mitochondrial superoxide production compared with their p53-null counterpart. This data was confirmed by stable H1299 cell lines expressing low levels of p53 specifically targeted to the matrix. Using immunoprecipitation and mass spectrometry, we identified the oligomycin sensitivity-conferring protein (OSCP), a subunit of the F₁F₀-ATP synthase complex, as a new partner of endogenous p53, specifically interacting with p53 localized in the matrix. Interestingly, this interaction seems implicated in mitochondrial p53 localization. Moreover, p53 localized in the matrix promotes the assembly of F₁F₀-ATP synthase. Taking into account that deregulations of mitochondrial respiration and reactive oxygen species production are tightly linked to cancer development, we suggest that mitochondrial p53 may be an important regulator of normal mitochondrial and cellular physiology, potentially exerting tumor suppression activity inside mitochondria.
authors: Laboratoire de génétique et biologie cellulaire (LGBC); Université de Versailles St Quentin-en-Yvelines/Ecole Pratique des Hautes Etudes; UFR des Sciences de la Santé; Montigny-le-Bretonneux, France.
authors: Marie
authors: M
authors: Bergeaud
authors: Lise
authors: L
authors: Mathieu
authors: Arnaud
authors: A
authors: Guillaume
authors: Ute M
authors: UM
authors: Moll
authors: Bernard
authors: B
authors: Mignotte
authors: Nathalie
authors: N
authors: Le Floch
authors: Jean-Luc
authors: JL
authors: Vayssière
authors: Vincent
authors: V
authors: Rincheval
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism; D019069:Cell Respiration / Q000235:genetics; D004795:Enzyme Stability; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism*; D008969:Molecular Sequence Data; D010101:Oxygen Consumption; D011485:Protein Binding / Q000235:genetics; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D000251:Adenosine Triphosphatases; C474451:F1F0-ATP synthase; D025261:Mitochondrial Proton-Translocating ATPases; C020439:oligomycin sensitivity-conferring protein
keywords: OSCP; cancer; energetic metabolism; mitochondria; oxidative phosphorylation; p53; reactive oxygen species; respiration; tumor suppressor
references: Biochim Biophys Acta. 2009 May;1787(5):328-34
references: 19413947
references: Circ Res. 2009 Sep 25;105(7):705-12, 11 p following 712
references: 19696408
references: FEBS Lett. 2004 Feb 13;559(1-3):171-4
references: 14960327
references: Nature. 1994 Jul 21;370(6486):220-3
references: 8028670
references: Hum Mol Genet. 2009 Dec 1;18(23):4552-64
references: 19779023
references: J Mol Biol. 2002 Aug 23;321(4):613-9
references: 12206777
references: BMC Cell Biol. 2009 Jun 25;10:50
references: 19555499
references: Science. 1991 Jul 5;253(5015):49-53
references: 1905840
references: Mol Cell Biol. 2006 Jun;26(12):4421-34
references: 16738310
references: J Cell Sci. 2012 May 15;125(Pt 10):2509-22
references: 22357944
references: Science. 2006 Jun 16;312(5780):1650-3
references: 16728594
references: J Biol Chem. 2000 May 26;275(21):16202-12
references: 10821866
references: EMBO J. 2005 Oct 5;24(19):3482-92
references: 16163384
references: J Biol Chem. 2006 Mar 31;281(13):8600-6
references: 16443602
references: Invest Ophthalmol Vis Sci. 2008 Oct;49(10):4237-44
references: 18487368
references: J Carcinog. 2009;8:8
references: 19439913
references: J Biol Chem. 2013 Feb 15;288(7):4723-32
references: 23271731
references: Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4570-1
references: 1647009
references: J Biol Chem. 2012 Feb 10;287(7):4426-33
references: 22157015
references: Biochem Cell Biol. 1997;75(4):351-8
references: 9493957
references: Cancer Res. 2005 May 1;65(9):3745-50
references: 15867370
references: Antioxid Redox Signal. 2001 Aug;3(4):611-23
references: 11554448
references: Cancer Res. 2003 Jul 1;63(13):3729-34
references: 12839966
references: J Cell Physiol. 2002 Jul;192(1):1-15
references: 12115731
references: Mol Cell. 2003 Mar;11(3):577-90
references: 12667443
references: Mol Cell Biol. 1984 Sep;4(9):1689-94
references: 6092932
references: Cell. 2012 Jun 22;149(7):1536-48
references: 22726440
references: J Biol Chem. 1997 Jun 13;272(24):15220-6
references: 9182545
references: Cancer Res. 2004 Apr 1;64(7):2350-6
references: 15059885
references: Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):633-40
references: 20116362
references: Science. 1990 Aug 31;249(4972):1046-9
references: 2144363
references: J Biol Chem. 2003 Jan 31;278(5):2963-8
references: 12433922
references: Nat Rev Mol Cell Biol. 2008 May;9(5):402-12
references: 18431400
references: J Biol Chem. 1995 Jul 14;270(28):16932-8
references: 7622511
references: EMBO J. 2000 Apr 17;19(8):1777-83
references: 10775262
references: Oncogene. 2010 Feb 25;29(8):1155-66
references: 19935715
references: J Biol Chem. 2008 Jul 25;283(30):21294-304
references: 18524770
references: Oncogene. 2004 Aug 26;23(39):6559-68
references: 15208669
references: Science. 1998 Nov 20;282(5393):1497-501
references: 9822382
references: Ann N Y Acad Sci. 2008 Dec;1147:293-302
references: 19076451
references: Cell Cycle. 2010 Mar 1;9(5):870-9
references: 20160511
references: Cell. 2009 May 1;137(3):413-31
references: 19410540
references: J Biol Chem. 2010 Mar 26;285(13):9835-9846
references: 20061391
references: Oncogene. 2002 Sep 5;21(39):6017-31
references: 12203114
references: Genes Dev. 1996 Oct 1;10(19):2438-51
references: 8843196
references: Nat Cell Biol. 2008 May;10(5):611-8
references: 18391940
references: Oncogene. 1999 Jan 7;18(1):127-37
references: 9926927
references: Science. 2009 Feb 6;323(5915):793-7
references: 19131594
references: Biochim Biophys Acta. 2009 Jun;1787(6):672-80
references: 19168025
references: Cancer Sci. 2004 Jan;95(1):7-11
references: 14720320
references: Leukemia. 1997 Apr;11 Suppl 3:337-9
references: 9209383
references: J Biol Chem. 2000 Aug 4;275(31):23471-5
references: 10816574
references: J Biol Chem. 2005 Dec 9;280(49):40398-401
references: 16207717
references: Oncogene. 2004 Aug 19;23(37):6226-36
references: 15247902
references: Biochim Biophys Acta. 1998 Oct 1;1400(1-3):139-54
references: 9748545
references: Mol Cell Biol. 2004 Aug;24(15):6728-41
references: 15254240
references: Cancer Res. 2006 Apr 1;66(7):3485-94
references: 16585172
references: Cancer Res. 2004 Apr 1;64(7):2627-33
references: 15059920
references: J Biol Chem. 2005 Aug 12;280(32):29346-54
references: 15914462
references: Nature. 1997 Sep 18;389(6648):300-5
references: 9305847
references: Cancer Res. 1993 May 15;53(10 Suppl):2212-6
references: 8485705
references: Science. 1990 Aug 31;249(4972):1049-51
references: 2144364
references: Oncogene. 2002 Oct 17;21(47):7195-204
references: 12370809
references: J Biol Chem. 1999 Apr 23;274(17):12061-6
references: 10207030
references: J Biol Chem. 2007 Oct 5;282(40):29193-200
references: 17699158
references: Nat Rev Cancer. 2009 Oct;9(10):691-700
references: 19759539
references: PLoS One. 2012;7(8):e43362
references: 22912861
references: Cell. 2012 Jun 8;149(6):1269-83
references: 22682249
references: AIDS. 2009 Apr 27;23(7):779-88
references: 19287302
references: Science. 1956 Aug 10;124(3215):269-70
references: 13351639
references: Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7455-60
references: 20378837
references: PLoS One. 2012;7(10):e47010
references: 23056559
references: Biochem Biophys Res Commun. 2009 Oct 2;387(4):772-7
references: 19635458
references: Nat Med. 2005 Dec;11(12):1306-13
references: 16286925
references: Science. 2004 Feb 13;303(5660):1010-4
references: 14963330
references: Genes Dev. 1995 Sep 1;9(17):2170-83
references: 7657168
references: Nat Genet. 1992 Apr;1(1):45-9
references: 1301998
references: Biochim Biophys Acta. 2009 May;1787(5):414-20
references: 19007744
references: Cell. 2006 Jul 14;126(1):107-20
references: 16839880
references: Nat Cell Biol. 2004 May;6(5):443-50
references: 15077116
references: Cell Growth Differ. 1996 Mar;7(3):301-10
references: 8838860
references: J Pathol. 2009 Sep;219(1):3-15
references: 19562738