title: Sepsis-induced Cardiac Mitochondrial Damage and Potential Therapeutic Interventions in the Elderly.
abstract: The incidence of sepsis and its attendant mortality risk are significantly increased with aging. Thus, severe sepsis in the elderly is likely to become an emerging concern in critical care units. Cardiac dysfunction is an important component of multi-organ failure after sepsis. In our laboratory, utilizing a pneumonia-related sepsis animal model, our research has been focused on the mechanisms underlying sepsis-induced cardiac failure. In this review, based on findings from others and ours, we discussed age-dependent decay in mitochondria and the role of mitochondrial reactive oxygen species (mtROS) in sepsis-induced cardiac inflammation and autophagy. Our recent discovery of a potential signal transduction pathway that triggers myocardial mitochondrial damage is also discussed. Because of the significance of mitochondria damage in the aging process and in sepsis pathogenesis, we hypothesize that specific enhancing mitochondrial antioxidant defense by mitochondria-targeted antioxidants (MTAs) may provide important therapeutic potential in treating elder sepsis patients. In this review, we summarized the categories of currently published MTA molecules and the results of preclinical evaluation of MTAs in sepsis and aging models.
authors.affiliation: Departments of Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.
authors.forename: Qun S
authors.initials: QS
authors.lastname: Zang
authors.affiliation: Departments of Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Wolf
authors.affiliation: Departments of Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Minei
keywords: autophagy; cardiac function; inflammation; mitochondria; mitochondria-targeted antioxidants; sepsis
references.citation: Science. 2005 Jun 24;308(5730):1909-11
references.pmid: 15879174
references.citation: Cardiovasc Res. 2010 Oct 1;88(1):83-92
references.pmid: 20558438
references.citation: J Biol Chem. 1997 Oct 10;272(41):25409-12
references.pmid: 9325246
references.citation: Pediatr Cardiol. 2011 Mar;32(3):282-9
references.pmid: 21249349
references.citation: JAMA. 2010 Oct 27;304(16):1787-94
references.pmid: 20978258
references.citation: Crit Care Med. 2007 Sep;35(9 Suppl):S584-90
references.pmid: 17713413
references.citation: Cardiovasc Res. 2012 Jan 1;93(1):79-88
references.pmid: 22012956
references.citation: Curr Opin Crit Care. 2009 Oct;15(5):392-7
references.pmid: 19633546
references.citation: J Mol Cell Cardiol. 2004 Jan;36(1):141-50
references.pmid: 14734056
references.citation: Antioxid Redox Signal. 2008 Mar;10(3):601-19
references.pmid: 17999629
references.citation: Surg Infect (Larchmt). 2007 Feb;8(1):41-54
references.pmid: 17381396
references.citation: J Gerontol. 1956 Jul;11(3):298-300
references.pmid: 13332224
references.citation: J Cell Biol. 2003 Mar 3;160(5):709-18
references.pmid: 12615910
references.citation: Autophagy. 2010 Jul;6(5):600-6
references.pmid: 20431347
references.citation: Cell Mol Life Sci. 2011 Aug;68(15):2603-13
references.pmid: 21063895
references.citation: Curr Drug Targets. 2009 Sep;10(9):872-80
references.pmid: 19799541
references.citation: Curr Opin Cardiol. 2011 May;26(3):216-22
references.pmid: 21415729
references.citation: Circulation. 2009 Oct 27;120(17):1695-703
references.pmid: 19822807
references.citation: Pharmacol Biochem Behav. 2010 Aug;96(2):211-6
references.pmid: 20470816
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13258-63
references.pmid: 21788490
references.citation: Exp Gerontol. 2002 Jan-Mar;37(2-3):235-47
references.pmid: 11772509
references.citation: Free Radic Biol Med. 2009 Mar 1;46(5):564-72
references.pmid: 19073249
references.citation: Endocr Metab Immune Disord Drug Targets. 2006 Jun;6(2):207-12
references.pmid: 16787296
references.citation: Mol Cell. 2010 Oct 22;40(2):280-93
references.pmid: 20965422
references.citation: J Clin Invest. 2001 Feb;107(4):485-93
references.pmid: 11181648
references.citation: Trends Immunol. 2006 Aug;27(8):352-7
references.pmid: 16807108
references.citation: Crit Care Med. 2001 Jul;29(7):1303-10
references.pmid: 11445675
references.citation: PLoS One. 2012;7(8):e43424
references.pmid: 22952679
references.citation: Circ Res. 2012 Apr 13;110(8):1109-24
references.pmid: 22499901
references.citation: Shock. 2005 Nov;24(5):495-9
references.pmid: 16247338
references.citation: Crit Care Med. 2004 Feb;32(2):342-9
references.pmid: 14758146
references.citation: Circ Res. 2007 Mar 30;100(6):914-22
references.pmid: 17332429
references.citation: Cell. 2008 Jan 11;132(1):27-42
references.pmid: 18191218
references.citation: J Exp Med. 1982 Jan 1;155(1):264-75
references.pmid: 6274994
references.citation: Cardiovasc Res. 2006 Dec 1;72(3):384-93
references.pmid: 17054926
references.citation: Annu Rev Immunol. 1994;12:991-1045
references.pmid: 8011301
references.citation: Am J Physiol Heart Circ Physiol. 2009 Feb;296(2):H470-9
references.pmid: 19098111
references.citation: Gastroenterol Clin North Am. 2001 Jun;30(2):313-34
references.pmid: 11432294
references.citation: Vaccine. 2000 Feb 25;18(16):1624-8
references.pmid: 10689139
references.citation: Lancet. 2002 Jul 20;360(9328):219-23
references.pmid: 12133657
references.citation: J Cardiovasc Transl Res. 2010 Aug;3(4):355-64
references.pmid: 20577843
references.citation: Burns. 2010 Mar;36(2):232-8
references.pmid: 19501973
references.citation: Free Radic Biol Med. 2002 Nov 1;33(9):1260-7
references.pmid: 12398934
references.citation: Am J Physiol Heart Circ Physiol. 2012 May 1;302(9):H1847-59
references.pmid: 22408027
references.citation: Annu Rev Immunol. 2009;27:229-65
references.pmid: 19302040
references.citation: J Appl Physiol (1985). 2007 Jan;102(1):44-53
references.pmid: 16916915
references.citation: Crit Care. 2002 Dec;6(6):500-8
references.pmid: 12493071
references.citation: J Clin Invest. 2003 Oct;112(7):983-5
references.pmid: 14523034
references.citation: Vaccine. 2000 Feb 25;18(16):1603-5
references.pmid: 10689135
references.citation: Trends Cell Biol. 2000 Apr;10(4):129-33
references.pmid: 10740266
references.citation: Nat Med. 2009 Oct;15(10):1170-8
references.pmid: 19767732
references.citation: J Surg Res. 2003 Feb;109(2):144-8
references.pmid: 12643856
references.citation: Cell. 2005 Sep 9;122(5):669-82
references.pmid: 16125763
references.citation: Biochem J. 2012 Jan 15;441(2):523-40
references.pmid: 22187934
references.citation: J Immunol. 2008 Jun 1;180(11):7485-96
references.pmid: 18490749
references.citation: Free Radic Res. 2009 Apr;43(4):323-8
references.pmid: 19235604
references.citation: Rheumatology (Oxford). 2005 Jan;44(1):32-9
references.pmid: 15367748
references.citation: Am J Physiol Heart Circ Physiol. 2003 Jul;285(1):H47-58
references.pmid: 12637356
references.citation: J Trauma. 1997 Mar;42(3):532-6
references.pmid: 9095123
references.citation: Exp Gerontol. 2000 Mar;35(2):119-31
references.pmid: 10767573
references.citation: J Biol Chem. 2006 Apr 14;281(15):10555-60
references.pmid: 16481327
references.citation: J Biol Chem. 2008 Sep 5;283(36):24406-11
references.pmid: 18583343
references.citation: Am J Respir Crit Care Med. 2001 Jan;163(1):218-25
references.pmid: 11208649
references.citation: J Burn Care Res. 2007 Nov-Dec;28(6):776-90
references.pmid: 17925660
references.citation: Biochemistry (Mosc). 2008 Dec;73(12):1273-87
references.pmid: 19120014
references.citation: Proc Natl Acad Sci U S A. 1999 Feb 2;96(3):846-51
references.pmid: 9927656
references.citation: Free Radic Biol Med. 2000 May 15;28(10):1547-54
references.pmid: 10927180
references.citation: Biogerontology. 2012 Dec;13(6):595-607
references.pmid: 23073710
references.citation: Nat Rev Immunol. 2009 Jul;9(7):465-79
references.pmid: 19521399
references.citation: J Surg Res. 1998 May;76(2):192-9
references.pmid: 9698522
references.citation: Int Immunol. 2001 Oct;13(10):1213-21
references.pmid: 11581166
references.citation: Circulation. 2009 Jun 2;119(21):2789-97
references.pmid: 19451351
references.citation: J Alzheimers Dis. 2010;21(2):479-91
references.pmid: 20555140
references.citation: Liver Int. 2010 Aug;30(7):1019-26
references.pmid: 20492507
references.citation: Immunity. 2011 May 27;34(5):651-64
references.pmid: 21616435
references.citation: Crit Care. 2008;12(6):R158
references.pmid: 19091069
references.citation: Eur J Nutr. 2012 Oct;51(7):769-81
references.pmid: 22684632
references.citation: Nature. 2012 May 10;485(7397):251-5
references.pmid: 22535248
references.citation: Crit Care Med. 2007 Jan;35(1):118-26
references.pmid: 17095947
references.citation: Mol Cell Proteomics. 2011 Feb;10(2):M110.000117
references.pmid: 20495213
references.citation: Physiol Rev. 2007 Jan;87(1):245-313
references.pmid: 17237347
references.citation: J Biol Chem. 2004 Sep 3;279(36):37575-87
references.pmid: 15220329
references.citation: Cell Mol Life Sci. 2005 Jul;62(13):1478-88
references.pmid: 15924266
references.citation: Arterioscler Thromb Vasc Biol. 2008 Apr;28(4):622-8
references.pmid: 18162611
references.citation: Nat Cell Biol. 2010 Sep;12(9):823-30
references.pmid: 20811354
references.citation: J Alzheimers Dis. 2010;20 Suppl 2:S609-31
references.pmid: 20463406
references.citation: Vaccine. 2000 Feb 25;18(16):1654-60
references.pmid: 10689144
references.citation: Free Radic Biol Med. 2008 Dec 1;45(11):1559-65
references.pmid: 18845241
references.citation: AAPS J. 2006 Apr 21;8(2):E277-83
references.pmid: 16796378
references.citation: Free Radic Biol Med. 2002 May 1;32(9):797-803
references.pmid: 11978481
references.citation: Crit Care Med. 2009 Jan;37(1):291-304
references.pmid: 19050640
references.citation: Mech Ageing Dev. 2010 Jun;131(6):415-21
references.pmid: 20600239
references.citation: Science. 2000 Sep 1;289(5484):1567-9
references.pmid: 10968795
references.citation: Diabetes. 2006 Mar;55(3):798-805
references.pmid: 16505246
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5407-12
references.pmid: 12697897
references.citation: FEBS Lett. 1997 Oct 6;415(3):294-8
references.pmid: 9357986
references.citation: J Clin Invest. 2007 Jul;117(7):1782-93
references.pmid: 17607355
references.citation: Intensive Care Med. 2004 Apr;30(4):527-9
references.pmid: 14985955
references.citation: Am J Physiol Cell Physiol. 2010 Mar;298(3):C740-8
references.pmid: 20007455
references.citation: J Leukoc Biol. 2008 Feb;83(2):245-53
references.pmid: 17984291
references.citation: Circ J. 2008;72 Suppl A:A31-7
references.pmid: 18772530
references.citation: Cardiovasc Res. 2009 Jun 1;82(3):448-57
references.pmid: 19293248
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):13807-12
references.pmid: 16174725
references.citation: Front Biosci (Elite Ed). 2009 Jun 01;1:277-87
references.pmid: 19482645
references.citation: Curr Opin Crit Care. 2003 Aug;9(4):266-70
references.pmid: 12883280
references.citation: Am J Physiol Regul Integr Comp Physiol. 2009 Oct;297(4):R1095-102
references.pmid: 19657095
references.citation: Shock. 2010 Jul;34(1):55-9
references.pmid: 19997055
references.citation: Aging Cell. 2009 Feb;8(1):73-5
references.pmid: 19077044
references.citation: Am J Clin Nutr. 1972 Aug;25(8):839-43
references.pmid: 5046729
references.citation: Aging (Albany NY). 2011 Nov;3(11):1110-9
references.pmid: 22166671
references.citation: Cardiovasc Res. 2008 Apr 1;78(1):26-35
references.pmid: 18194990
references.citation: Circ Res. 2010 Jul 9;107(1):106-16
references.pmid: 20448215
references.citation: Ann Surg. 2011 Jun;253(6):1190-200
references.pmid: 21412148
references.citation: Chest. 1992 Jun;101(6):1644-55
references.pmid: 1303622
references.citation: Gerontology. 1987;33(1):34-9
references.pmid: 3596262
references.citation: Cell. 2006 Feb 24;124(4):783-801
references.pmid: 16497588
references.citation: Vaccine. 2000 Feb 25;18(16):1717-20
references.pmid: 10689155
references.citation: Biochemistry (Mosc). 2010 Mar;75(3):274-80
references.pmid: 20370605
references.citation: Respir Physiol. 1987 Dec;70(3):275-86
references.pmid: 2961036
references.citation: Biochem J. 2010 Nov 15;432(1):9-19
references.pmid: 20825366
references.citation: PLoS One. 2012;7(10):e47265
references.pmid: 23056618
references.citation: Antioxid Redox Signal. 2014 Jan 20;20(3):507-18
references.pmid: 23641894
references.citation: Apoptosis. 2010 Feb;15(2):139-52
references.pmid: 19851871
references.citation: Mitochondrion. 2002 Feb;1(4):339-48
references.pmid: 16120288
references.citation: Crit Care Med. 2010 Feb;38(2):367-74
references.pmid: 20035219
references.citation: Free Radic Biol Med. 2002 Sep 15;33(6):774-97
references.pmid: 12208366
references.citation: Free Radic Biol Med. 2005 May 15;38(10):1278-95
references.pmid: 15855047
references.citation: Gerontology. 1995;41 Suppl 2:69-79
references.pmid: 8821322
references.citation: Ann N Y Acad Sci. 2010 Jul;1201:96-103
references.pmid: 20649545
references.citation: J Physiol. 2006 Jul 1;574(Pt 1):33-9
references.pmid: 16709637
references.citation: J Biol Chem. 2003 Jul 18;278(29):27251-5
references.pmid: 12759343
references.citation: Am J Physiol Cell Physiol. 2010 Oct;299(4):C770-8
references.pmid: 20686066
references.citation: J Am Geriatr Soc. 2001 Jul;49(7):934-40
references.pmid: 11527485
references.citation: Exp Hematol. 2005 Jan;33(1):73-84
references.pmid: 15661400
references.citation: Biophys J. 2009 Feb 18;96(4):1388-98
references.pmid: 19217856
references.citation: FEBS Lett. 2008 Apr 2;582(7):1104-10
references.pmid: 18331841
references.citation: Am J Anat. 1977 Sep;150(1):63-71
references.pmid: 930852
references.citation: Crit Care. 2003 Apr;7(2):139-45
references.pmid: 12720560
references.citation: FEBS Lett. 2007 Dec 11;581(29):5579-85
references.pmid: 17997986
references.citation: Free Radic Biol Med. 2012 Sep 15;53(6):1327-38
references.pmid: 22902401
references.citation: Chest. 1999 May;115(5 Suppl):71S-76S
references.pmid: 10331337
references.citation: Cell Metab. 2007 Feb;5(2):151-6
references.pmid: 17276357
references.citation: Circ Res. 2011 Apr 1;108(7):837-46
references.pmid: 21311045
references.citation: Nature. 2011 Jan 20;469(7330):323-35
references.pmid: 21248839
references.citation: Adv Immunol. 2002;80:243-84
references.pmid: 12078483
references.citation: Int J Immunopathol Pharmacol. 2009 Apr-Jun;22(2):311-22
references.pmid: 19505385
references.citation: J Intensive Care Med. 2012 May-Jun;27(3):179-83
references.pmid: 21436163
references.citation: Annu Rev Biochem. 2007;76:447-80
references.pmid: 17328678
references.citation: Nature. 1999 Dec 9;402(6762):672-6
references.pmid: 10604474
references.citation: J Biol Chem. 1991 Nov 15;266(32):22028-34
references.pmid: 1657986
references.citation: Ann N Y Acad Sci. 1998 Nov 20;854:224-38
references.pmid: 9928433
references.citation: J Neurochem. 2004 Apr;89(1):248-56
references.pmid: 15030409
references.citation: Shock. 2009 Sep;32(3):239-46
references.pmid: 19106815
references.citation: J Mol Cell Cardiol. 2000 Jan;32(1):161-75
references.pmid: 10652200
references.citation: Methods Enzymol. 2009;453:343-63
references.pmid: 19216915
references.citation: Crit Care Med. 2007 Jun;35(6):1599-608
references.pmid: 17452940
references.citation: Crit Care. 2007;11(4):R73
references.pmid: 17617901
references.citation: Shock. 2007 Jul;28(1):24-8
references.pmid: 17483747
references.citation: Lab Invest. 2009 May;89(5):549-61
references.pmid: 19188912
references.citation: J Biol Chem. 2003 Sep 19;278(38):36027-31
references.pmid: 12840017
references.citation: J Infect Dis. 1999 Aug;180(2):551-4
references.pmid: 10395881
references.citation: Crit Care Med. 2006 Jan;34(1):15-21
references.pmid: 16374151
references.citation: Cell Metab. 2010 Dec 1;12(6):668-74
references.pmid: 21109199
references.citation: Biochim Biophys Acta. 2012 May;1817(5):718-25
references.pmid: 22321370
references.citation: Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20388-93
references.pmid: 19918053
references.citation: FASEB J. 2003 Oct;17(13):1972-4
references.pmid: 12923074
references.citation: Shock. 2011 May;35(5):506-11
references.pmid: 21263383
references.citation: J Cell Biochem. 2008 Jun 1;104(3):840-9
references.pmid: 18247338
references.citation: Free Radic Biol Med. 2010 Dec 1;49(11):1674-84
references.pmid: 20828611
references.citation: Nature. 2011 Jan 13;469(7329):221-5
references.pmid: 21124315
references.citation: Annu Rev Pharmacol Toxicol. 2007;47:629-56
references.pmid: 17014364
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9745-50
references.pmid: 18621691
references.citation: Crit Care Med. 2006 Sep;34(9 Suppl):S176-82
references.pmid: 16917421
references.citation: FASEB J. 2005 Mar;19(3):419-21
references.pmid: 15642720
references.citation: Shock. 2012 Mar;37(3):289-96
references.pmid: 22089196
references.citation: Free Radic Biol Med. 2005 Sep 1;39(5):567-83
references.pmid: 16085176
references.citation: Biochim Biophys Acta. 2006 Dec;1763(12):1755-66
references.pmid: 17034877
references.citation: Cell Signal. 2013 Jan;25(1):50-65
references.pmid: 23000343
references.citation: Free Radic Biol Med. 2002 Sep 1;33(5):611-9
references.pmid: 12208347
references.citation: Aging (Albany NY). 2009 Jun 29;1(7):664-8
references.pmid: 20157547
references.citation: FASEB J. 2005 Jul;19(9):1088-95
references.pmid: 15985532
references.citation: Ann N Y Acad Sci. 2007 Apr;1100:505-9
references.pmid: 17460215
references.citation: J Mol Med (Berl). 2006 Sep;84(9):712-25
references.pmid: 16924467
references.citation: J Biol Chem. 2004 Jun 18;279(25):26036-45
references.pmid: 15056672
references.citation: Ann Intern Med. 1990 Aug 1;113(3):227-42
references.pmid: 2197912
references.citation: J Leukoc Biol. 2004 Aug;76(2):291-9
references.pmid: 15039467
references.citation: Nature. 2010 Mar 4;464(7285):104-7
references.pmid: 20203610
references.citation: Am J Med. 2007 Dec;120(12):1012-22
references.pmid: 18060918