title: Upregulation of the mitochondrial Lon Protease allows adaptation to acute oxidative stress but dysregulation is associated with chronic stress, disease, and aging.
abstract: The elimination of oxidatively modified proteins is a crucial process in maintaining cellular homeostasis, especially during stress. Mitochondria are protein-dense, high traffic compartments, whose polypeptides are constantly exposed to superoxide, hydrogen peroxide, and other reactive species, generated by 'electron leakage' from the respiratory chain. The level of oxidative stress to mitochondrial proteins is not constant, but instead varies greatly with numerous metabolic and environmental factors. Oxidized mitochondrial proteins must be removed rapidly (by proteolytic degradation) or they will aggregate, cross-link, and cause toxicity. The Lon Protease is a key enzyme in the degradation of oxidized proteins within the mitochondrial matrix. Under conditions of acute stress Lon is highly inducible, possibly with the oxidant acting as the signal inducer, thereby providing increased protection. It seems that under chronic stress conditions, however, Lon levels actually decline. Lon levels also decline with age and with senescence, and senescent cells even lose the ability to induce Lon during acute stress. We propose that the regulation of Lon is biphasic, in that it is up-regulated during transient stress and down-regulated during chronic stress and aging, and we suggest that the loss of Lon responsiveness may be a significant factor in aging, and in age-related diseases.
authors.affiliation: Ethel Percy Andrus Gerontology Center of the Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089-0191, USA.
authors.forename: Jenny K
authors.initials: JK
authors.lastname: Ngo
authors.forename: Laura C D
authors.initials: LC
authors.lastname: Pomatto
authors.forename: Kelvin J A
authors.initials: KJ
authors.lastname: Davies
mesh_terms: D000220:Adaptation, Biological; D000375:Aging / Q000378:metabolism*; D000818:Animals; D004194:Disease; D006801:Humans; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism; D018384:Oxidative Stress; D049070:Protease La / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D049070:Protease La
keywords: 2D-PAGE, two-dimensional polyacrylamide gel electrophoresis; AAA, ATPases associated with diverse cellular activities; Aco1, Aconitase 1; Adaptation; CDDO, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; CDDO-Me, methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate; COX, cytochrome c oxidase; COX4-1, cytochrome c oxidase subunit IV isoform 1; COX4-2, cytochrome c oxidase subunit IV isoform 2; Ccp1, mitochondrial cytochrome-c peroxidase; Clp, caseinolytic protease; ClpP, core catalytic protease unit; ERAD, endoplasmic reticulum-associated degradation; FRDA, Friedreich's ataxia; Fe/S, iron/SULFUR; HAART, highly active antiretroviral therapy; HIF-1, hypoxia inducible factor-1; HSP104, heat shock protein 104; HSP60, heat shock protein 60; Hormesis; HsIVU, bacterial ATP-dependent protease; Lon Protease; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; MPPβ, mitochondrial processing peptidase beta subunit; Mitochondria; NRF-2, nuclear factor (erythroid-derived 2)-like 2; Nfκb, nuclear factor kappa-light-chain-enhancer of activated B csells; Oxidative stress; PRSS15, LON gene; Pim1, ATP-dependent Lon protease from yeast; Protease La, ATP-dependent protease; Protein degradation and oxidation; Prx1, mitochondrial peroxiredoxin 1; SLLVY-AMC, N-succinyl-Leu-Leu-Val-Tyr-7-amino-4-methylcoumarin; SOD, cytosolic superoxide dismutase; SOD2, mitochondrial superoxide dismutase 2; SPG13, hereditary spastic paraplegia; WI-38, human lung fibroblast; Yjl200c, mitochondrial aconitase isozyme
references.citation: J Biol Chem. 2004 Apr 2;279(14):13902-10
references.pmid: 14739292
references.citation: Curr Pharm Des. 2005;11(11):1451-7
references.pmid: 15853675
references.citation: EMBO J. 1994 Nov 1;13(21):5135-45
references.pmid: 7957078
references.citation: Annu Rev Biochem. 1992;61:1175-212
references.pmid: 1497308
references.citation: J Neurochem. 2006 Jun;97(6):1659-75
references.pmid: 16805775
references.citation: Free Radic Biol Med. 1988;5(4):215-23
references.pmid: 2908182
references.citation: Ann Neurol. 1984 Oct;16(4):481-8
references.pmid: 6093682
references.citation: J Neurochem. 2002 Mar;80(5):780-7
references.pmid: 11948241
references.citation: J Biol Chem. 1996 Apr 26;271(17):10137-42
references.pmid: 8626573
references.citation: Ann N Y Acad Sci. 2002 Apr;959:199-213
references.pmid: 11976197
references.citation: Exp Gerontol. 2004 Aug;39(8):1117-23
references.pmid: 15359468
references.citation: PLoS Biol. 2004 Jun;2(6):e160
references.pmid: 15208715
references.citation: J Proteome Res. 2008 Dec;7(12):5138-47
references.pmid: 19367701
references.citation: Free Radic Biol Med. 2002 Jun 1;32(11):1084-9
references.pmid: 12031893
references.citation: Arch Biochem Biophys. 2012 Jul 15;523(2):181-90
references.pmid: 22564544
references.citation: Nat Cell Biol. 2002 Sep;4(9):674-80
references.pmid: 12198491
references.citation: J Biol Chem. 1996 Nov 1;271(44):27730-8
references.pmid: 8910366
references.citation: J Gerontol A Biol Sci Med Sci. 2011 Nov;66(11):1178-85
references.pmid: 21868393
references.citation: J Biol Chem. 1998 Aug 7;273(32):20596-602
references.pmid: 9685417
references.citation: J Neurol Sci. 2010 Aug 15;295(1-2):46-52
references.pmid: 20570288
references.citation: Hum Mol Genet. 2001 Sep 15;10(19):2061-7
references.pmid: 11590123
references.citation: Cell. 2007 Apr 6;129(1):111-22
references.pmid: 17418790
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18503-8
references.pmid: 19841274
references.citation: Free Radic Res. 2006 Dec;40(12):1269-76
references.pmid: 17090416
references.citation: Free Radic Biol Med. 2013 Mar;56:9-16
references.pmid: 23220263
references.citation: Mol Endocrinol. 2003 Dec;17(12):2461-76
references.pmid: 12958217
references.citation: Biochimie. 2008 Feb;90(2):260-9
references.pmid: 18021745
references.citation: Antioxid Redox Signal. 2010 Aug 15;13(4):539-49
references.pmid: 19958171
references.citation: Nat Cell Biol. 2009 Jul;11(7):852-8
references.pmid: 19543272
references.citation: Science. 1994 Apr 8;264(5156):273-6
references.pmid: 8146662
references.citation: Eur J Biochem. 2002 Jan;269(2):451-7
references.pmid: 11856303
references.citation: FEBS J. 2009 Feb;276(4):1036-47
references.pmid: 19154341
references.citation: J Biol Chem. 2012 Mar 23;287(13):10021-10031
references.pmid: 22308036
references.citation: AIDS. 2004 Jan 23;18(2):137-51
references.pmid: 15075530
references.citation: Int J Biochem Cell Biol. 2004 Dec;36(12):2519-30
references.pmid: 15325589
references.citation: Arch Toxicol. 2001 Sep;75(7):425-38
references.pmid: 11693184
references.citation: Methods Enzymol. 1994;233:346-57
references.pmid: 8015469
references.citation: Mol Cell Biol. 2006 Feb;26(3):762-76
references.pmid: 16428434
references.citation: J Biol Chem. 1994 Jan 7;269(1):238-42
references.pmid: 8276800
references.citation: AIDS. 2010 Mar 27;24(6):841-50
references.pmid: 20168207
references.citation: Science. 1999 Aug 27;285(5432):1390-3
references.pmid: 10464095
references.citation: Eur J Biochem. 2003 May;270(10):2295-302
references.pmid: 12752449
references.citation: FEBS Lett. 1999 Feb 12;444(2-3):186-8
references.pmid: 10050756
references.citation: Mikrobiologiia. 1980 May-Jun;49(3):373-6
references.pmid: 7402116
references.citation: J Biol Chem. 2005 Jul 1;280(26):25103-10
references.pmid: 15870080
references.citation: Physiol Rev. 1998 Apr;78(2):547-81
references.pmid: 9562038
references.citation: Biochim Biophys Acta. 2006 May-Jun;1757(5-6):700-7
references.pmid: 16782042
references.citation: Toxicol Sci. 2008 Feb;101(2):341-9
references.pmid: 17975114
references.citation: Biochemistry. 2003 Dec 23;42(50):14846-55
references.pmid: 14674759
references.citation: Mol Biol Cell. 2011 Mar 1;22(5):541-54
references.pmid: 21209324
references.citation: Neurochem Int. 2008 Sep;53(3-4):95-101
references.pmid: 18598728
references.citation: FEBS Lett. 2002 Aug 28;526(1-3):66-70
references.pmid: 12208506
references.citation: Ann N Y Acad Sci. 2007 Nov;1119:88-96
references.pmid: 18056958
references.citation: EMBO J. 2005 Apr 6;24(7):1311-7
references.pmid: 15775985
references.citation: Genes Dev. 1998 May 15;12(10):1515-24
references.pmid: 9585511
references.citation: Antioxid Redox Signal. 2006 Jan-Feb;8(1-2):205-16
references.pmid: 16487054
references.citation: Neuroscience. 2008 May 2;153(2):474-82
references.pmid: 18378094
references.citation: Adv Exp Med Biol. 2007;594:167-89
references.pmid: 17205684
references.citation: Lancet. 1999 Sep 25;354(9184):1112-5
references.pmid: 10509516
references.citation: Arch Biochem Biophys. 1995 Apr 1;318(1):231-40
references.pmid: 7726566
references.citation: Blood. 2012 Apr 5;119(14):3321-9
references.pmid: 22323447
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3540-5
references.pmid: 20133687
references.citation: J Biol Chem. 1985 Oct 5;260(22):12029-34
references.pmid: 2931432
references.citation: Circ Res. 2012 Apr 27;110(9):1174-8
references.pmid: 22456183
references.citation: Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):5987-91
references.pmid: 15840721
references.citation: Free Radic Biol Med. 2005 Mar 1;38(5):665-77
references.pmid: 15683722
references.citation: Free Radic Biol Med. 2009 Apr 15;46(8):1042-8
references.pmid: 19439239
references.citation: J Biol Chem. 2010 Apr 9;285(15):11445-57
references.pmid: 20150421
references.citation: J Biol Chem. 2002 Nov 29;277(48):45829-37
references.pmid: 12237310
references.citation: J Exp Biol. 2013 Feb 15;216(Pt 4):543-53
references.pmid: 23038734
references.citation: Toxicol Appl Pharmacol. 2008 Aug 15;231(1):43-51
references.pmid: 18495193
references.citation: Biochem J. 2010 Dec 15;432(3):585-94
references.pmid: 20919990
references.citation: Science. 1997 Aug 1;277(5326):653-9
references.pmid: 9235882
references.citation: J Bacteriol. 2005 Jun;187(12):4207-13
references.pmid: 15937182
references.citation: Gene. 2003 Mar 13;306:45-55
references.pmid: 12657466
references.citation: Toxicol Lett. 2005 Jan 15;155(1):41-50
references.pmid: 15585358
references.citation: Exp Gerontol. 2006 Jul;41(7):653-7
references.pmid: 16677792
references.citation: Nat Cell Biol. 2011 Nov 27;14(1):93-105
references.pmid: 22119785
references.citation: Proteomics. 2010 Apr;10(7):1426-43
references.pmid: 20186747
references.citation: Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18410-5
references.pmid: 20930118
references.citation: Science. 1997 Jun 13;276(5319):1709-12
references.pmid: 9180083
references.citation: Mitochondrion. 2011 Jan;11(1):200-6
references.pmid: 20933102
references.citation: Eur J Biochem. 2004 Nov;271(22):4559-64
references.pmid: 15560797
references.citation: Trends Biochem Sci. 1997 Apr;22(4):118-23
references.pmid: 9149530
references.citation: FEBS Lett. 2002 Dec 4;532(1-2):103-6
references.pmid: 12459471
references.citation: Aging Cell. 2010 Apr;9(2):252-72
references.pmid: 20102351
references.citation: FEBS Lett. 2005 Dec 19;579(30):6846-50
references.pmid: 16337203
references.citation: J Cell Biol. 2002 Jun 24;157(7):1151-60
references.pmid: 12082077
references.citation: Biochim Biophys Acta. 2006 May-Jun;1763(5-6):422-9
references.pmid: 16725216
references.citation: J Biol Chem. 2002 Dec 6;277(49):47946-53
references.pmid: 12381727
references.citation: Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):6678-82
references.pmid: 10359771
references.citation: Bioorg Med Chem Lett. 2005 May 2;15(9):2215-9
references.pmid: 15837296
references.citation: Free Radic Biol Med. 2013 Feb;55:109-18
references.pmid: 23142766