Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Critical Care
Published in: Critical Care 4/2010

01-08-2010 | Review

Bench-to-bedside review: Targeting antioxidants to mitochondria in sepsis

Author: Helen F Galley

Published in: Critical Care | Issue 4/2010

Login to get access

Abstract

Development of organ dysfunction associated with sepsis is now accepted to be due at least in part to oxidative damage to mitochondria. Under normal circumstances, complex interacting antioxidant defense systems control oxidative stress within mitochondria. However, no studies have yet provided conclusive evidence of the beneficial effect of antioxidant supplementation in patients with sepsis. This may be because the antioxidants are not accumulating in the mitochondria, where they are most needed. Antioxidants can be targeted selectively to mitochondria by several means. This review describes the in vitro studies and animal models of several diseases involving oxidative stress, including sepsis, in which antioxidants targeted at mitochondria have shown promise, and the future implications for such approaches in patients.
Appendix
Available only for authorised users
Literature
1.
Marshall JC, Vincent JL, Guyatt G, Angus DC, Abraham E, Bernard G, Bombardier C, Calandra T, Jørgensen HS, Sylvester R, Boers M: Outcome measures for clinical research in sepsis: a report of the 2 nd Cambridge Colloquium of the International Sepsis Forum. Crit Care Med 2005, 33: 1708-1716. 10.1097/01.CCM.0000174478.70338.03CrossRefPubMed
2.
3.
4.
Bayir H, Kagan VE: Mitochondrial injury, oxidative stress and apoptosis-there is nothing as practical as a good theory. Crit Care 2008, 12: 206. 10.1186/cc6779PubMedCentralCrossRefPubMed
5.
Ghafourifar P, Cadenas E: Mitochondrial nitric oxide synthase. Trends Pharmacol Sci 2005, 26: 190-195. 10.1016/j.tips.2005.02.005CrossRefPubMed
6.
Lacza Z, Pankotai E, Csordás A, Gero D, Kiss L, Horváth EM, Kollai M, Busija DW, Szabó C: Mitochondrial NO and reactive nitrogen species production: does mtNOS exist? Nitric Oxide 2006, 14: 162-168. 10.1016/j.niox.2005.05.011CrossRefPubMed
7.
Poyton RO, Ball KA, Castello PR: Mitochondrial generation of free radicals and hypoxic signaling. Trends Endocrinol Metab 2009, 20: 332-340. 10.1016/j.tem.2009.04.001CrossRefPubMed
8.
Qunitero M, Colombo SL, Godfrey A, Moncada S: Mitochondria as signaling organelles in the vascular endothelium. Proc Natl Acad Sci USA 2006, 103: 5379-5384. 10.1073/pnas.0601026103CrossRef
9.
10.
James AM, Murphy MP: How mitochondrial damage affects cell function. J Biomed Sci 2002, 9: 475-487. 10.1007/BF02254975CrossRefPubMed
11.
Zhang H, Go YM, Jones DP: Mitochondrial thioredoxin-2/peroxiredoxin-3 system functions in parallel with mitochondrial GSH system in protection against oxidative stress. Arch Biochem Biophys 2007, 465: 119-126. 10.1016/j.abb.2007.05.001CrossRefPubMed
12.
13.
Fariss MW, Chan CB, Patel M, Van Houten B, Orrenius S: Role of mitochondria in toxic oxidative stress. Mol Interv 2005, 5: 94-111. 10.1124/mi.5.2.7CrossRefPubMed
14.
Mishra V: Oxidative stress and role of antioxidant supplementation in critical illness. Clin Lab 2007, 53: 199-209.PubMed
15.
Goode HF, Cowley HC, Walker BE, Webster NR: Decreased antioxidant status and increased lipid peroxidation in patients with sepsis and secondary organ dysfunction. Crit Care Med 1995, 23: 646-651. 10.1097/00003246-199504000-00011CrossRefPubMed
16.
Galley HF, Davies MJ, Webster NR: Xanthine oxidase activity and free radical generation in patients with sepsis syndrome. Crit Care Med 1996, 24: 1649-1653. 10.1097/00003246-199610000-00008CrossRefPubMed
17.
Hill AL, Lowes DA, Webster NR, Sheth CC, Gow NA, Galley HF: Regulation of pentraxin-3 by antioxidants. Br J Anaesth 2009, 103: 833-839. 10.1093/bja/aep298PubMedCentralCrossRefPubMed
18.
Cowley HC, Bacon PJ, Goode HF, Webster NR, Jones JG, Menon DK: Plasma antioxidant potential in sepsis: A comparison of survivors and non-survivors. Crit Care Med 1996, 24: 1179-1183. 10.1097/00003246-199607000-00019CrossRefPubMed
19.
Chuang CC, Shiesh SC, Chi CH, Tu YF, Hor LI, Shieh CC, Chen MF: Serum total antioxidant capacity reflects severity of illness in patients with severe sepsis. Crit Care 2006, 10: R36. 10.1186/cc4826PubMedCentralCrossRefPubMed
20.
Borrelli E, Roux-Lombard P, Grau GE, Girardin E, Ricou B, Dayer J, Suter PM: Plasma concentrations of cytokines, their soluble receptors, and antioxidant vitamins can predict the development of multiple organ failure in patients at risk. Crit Care Med 1996, 24: 392-397. 10.1097/00003246-199603000-00006CrossRefPubMed
21.
Cross CE, Forte T, Stocker R, Louie S, Yamamoto Y, Ames BN, Frei B: Oxidative stress and abnormal cholesterol metabolism in patients with adult respiratory distress syndrome. J Lab Clin Med 1990, 115: 396-404.PubMed
22.
Galley HF, Webster NR: Elevated serum bleomycin-detectable iron concentrations in patients with sepsis syndrome. Intensive Care Med 1996, 22: 226-229. 10.1007/BF01712241CrossRefPubMed
23.
Galley HF, Davies MJ, Webster NR: Ascorbyl radical formation in patients with sepsis: effect of ascorbate loading. Free Radic Biol Med 1996,20(1):139-143. 10.1016/0891-5849(95)02022-5CrossRefPubMed
24.
25.
Arnalich F, Garcia-Palomero E, Lopez J: Predictive value of NFκB activity and plasma cytokine levels in patients with sepsis. Infect Immun 2000, 68: 1942-1945. 10.1128/IAI.68.4.1942-1945.2000PubMedCentralCrossRefPubMed
26.
Paterson RL, Galley HF, Dhillon JK, Webster NR: Increased NFκB activation in critically ill patients who die. Crit Care Med 2000, 28: 1047-1051. 10.1097/00003246-200004000-00022CrossRefPubMed
27.
Crouser ED: Mitochondrial dysfunction in septic shock and multiple organ dysfunction syndrome. Mitochondrion 2004, 4: 729-741. 10.1016/j.mito.2004.07.023CrossRefPubMed
28.
Brealey D, Singer M: Mitochondrial dysfunction in sepsis. Curr Infect Dis Rep 2003, 5: 365-371. 10.1007/s11908-003-0015-9CrossRefPubMed
29.
Brealey D, Karyampudi S, Jacques TS, Novelli M, Stidwill R, Taylor V, Smolenski RT, Singer M: Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure. Am J Physiol Regul Integr Comp Physiol 2004, 286: R491-497.CrossRefPubMed
30.
Gellerich FN, Trumbeckaite S, Hertel K, Zierz S, Müller-Werdan U, Werdan K, Redl H, Schlag G: Impaired energy metabolism in hearts of septic baboons: diminished activities of Complex I and Complex II of the mitochondrial respiratory chain. Shock 1999, 11: 336-341. 10.1097/00024382-199905000-00006CrossRefPubMed
31.
Crouser ED, Julian MW, Blaho DV, Pfeiffer DR: Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity. Crit Care Med 2002, 30: 276-284. 10.1097/00003246-200202000-00002CrossRefPubMed
32.
Vanhorebeek I, De Vos R, Mesotten D, Wouters PJ, De Wolf-Peeters C, Van den Berghe G: Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients. Lancet 2005, 365: 53-59. 10.1016/S0140-6736(04)17665-4CrossRefPubMed
33.
Yassen K, Galley HF, Lee A, Webster NR: Mitochondrial redox state in the critically ill. Br J Anaesth 1999, 83: 325-327.CrossRefPubMed
34.
Brealey D, Brand M, Hargreaves I, Heales S, Land J, Smolenski R, Davies NA, Cooper CE, Singer M: Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 2002, 360: 219-223. 10.1016/S0140-6736(02)09459-XCrossRefPubMed
35.
Rinaldi S, Landucci F, De Gaudio AR: Antioxidant therapy in critically ill septic patients. Curr Drug Targets 2009, 10: 872-880. 10.2174/138945009789108774CrossRefPubMed
36.
Smith RAJ, Porteous AM, Coulter CV, Murphy MP: Selective targeting of an antioxidant to mitochondria. Eur J Biochem 1999, 263: 709-716. 10.1046/j.1432-1327.1999.00543.xCrossRefPubMed
37.
Kelso GF, Porteous CM, Coulter CV, Hughes G, Porteous WK, Ledgerwood EC, Smith RA, Murphy MP: Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. J Biol Chem 2001, 276: 4588-4596. 10.1074/jbc.M009093200CrossRefPubMed
38.
Dhanasekaran A, Kotamraju S, Kalivendi SV, Matsunaga T, Shang T, Keszler A, Joseph J, Kalyanaraman B: Supplementation of endothelial cells with mitochondria-targeted antioxidants inhibit peroxide-induced mitochondrial iron uptake, oxidative damage, and apoptosis. J Biol Chem 2004, 279: 37575-37587. 10.1074/jbc.M404003200CrossRefPubMed
39.
Bedogni B, Pani G, Colavitti R, Riccio A, Borrello S, Murphy M, Smith R, Eboli ML, Galeotti T: Redox regulation of cAMP-responsive element-binding protein and induction of manganous superoxide dismutase in nerve growth factor-dependent cell survival. J Biol Chem 2003, 278: 16510-16519. 10.1074/jbc.M301089200CrossRefPubMed
40.
Smith RAJ, Porteous C, Gane AM, Murphy MP: Delivery of bioactive molecules to mitochondria in vivo . Proc Natl Acad Sci USA 2003, 100: 5407-5412. 10.1073/pnas.0931245100PubMedCentralCrossRefPubMed
41.
González-Rubio S, Hidalgo AB, Ferrín G, Bello RI, González R, Gahete MD, Ranchal I, Rodríguez BA, Barrera P, Aguilar-Melero P, Linares CI, Castaño JP, Victor VM, De la Mata M, Muntané J: Mitochondrial-driven ubiquinone enhances extracellular calcium-dependent nitric oxide production and reduces glycochenodeoxycholic acid-induced cell death in hepatocytes. Chem Res Toxicol 2009, 22: 1984-1991. 10.1021/tx900327tCrossRefPubMed
42.
Adlam VJ, Harrison JC, Porteous CM, James AM, Smith RA, Murphy MP, Sammut IA: Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury. FASEB J 2005, 19: 1088-1095. 10.1096/fj.05-3718comCrossRefPubMed
43.
Graham D, Huynh NN, Hamilton CA, Beattie E, Smith RA, Cochemé HM, Murphy MP, Dominiczak AF: Mitochondria-targeted antioxidant MitoQ10 improves endothelial function and attenuates cardiac hypertrophy. Hypertension 2009, 54: 322-328. 10.1161/HYPERTENSIONAHA.109.130351CrossRefPubMed
44.
Esplugues JV, Rocha M, Nuñez C, Bosca I, Ibiza S, Herance JR, Ortega A, Serrador JM, D'Ocon P, Victor VM: Complex I dysfunction and tolerance to nitroglycerin: an approach based on mitochondrial-targeted antioxidants. Circ Res 2006, 99: 1067-1075. 10.1161/01.RES.0000250430.62775.99CrossRefPubMed
45.
46.
47.
Filipovska A, FkaKelso GF, Brown SE, Beer SM, Smith RAJ, Murphy MP: Synthesis and characterization of a triphenylphosphonium-conjugated peroxidase mimetic. J Biol Chem 2005, 280: 24113-24126. 10.1074/jbc.M501148200CrossRefPubMed
48.
Skulachev VP, Anisimov VN, Antonenko YN, Bakeeva LE, Chernyak BV, Erichev VP, Filenko OF, Kalinina NI, Kapelko VI, Kolosova NG, Kopnin BP, Korshunova GA, Lichinitser MR, Obukhova LA, Pasyukova EG, Pisarenko OI, Roginsky VA, Ruuge EK, Senin II, Severina II, Skulachev MV, Spivak IM, Tashlitsky VN, Tkachuk VA, Vyssokikh MY, Yaguzhinsky LS, Zorov DB: An attempt to prevent senescence: a mitochondrial approach. Biochim Biophys Acta 2009, 1787: 437-461. 10.1016/j.bbabio.2008.12.008CrossRefPubMed
49.
Wipf P, Xiao J, Jiang J, Belikova NA, Tyurin VA, Fink MP, Kagan VE: Mitochondrial targeting of selective electron scavengers: synthesis and biological analysis of hemigramicidin-TEMPOL conjugates. J Am Chem Soc 2005, 127: 12460-12461. 10.1021/ja053679lCrossRefPubMed
50.
Fink MP, Macias CA, Xiao J, Tyurina YY, Delude RL, Greenberger JS, Kagan VE, Wipf P: Hemigramicidin-TEMPOL conjugates: novel mitochondria-targeted antioxidants. Crit Care Med 2007, 35: S461-467. 10.1097/01.CCM.0000279192.96303.E7CrossRefPubMed
51.
Macias CA, Chiao JW, Xiao J, Arora DS, Tyurina YY, Delude RL, Wipf P, Kagan VE, Fink MP: Treatment with a novel hemigramicidin-TEMPO conjugate prolongs survival in a rat model of lethal hemorrhagic shock. Ann Surg 2007, 245: 305-314. 10.1097/01.sla.0000236626.57752.8ePubMedCentralCrossRefPubMed
52.
Zhao K, Zhao GM, Wu D, Soong Y, Birk AV, Schiller PW, Szeto HH: Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. J Biol Chem 2004, 279: 34682-34690. 10.1074/jbc.M402999200CrossRefPubMed
53.
Sheu SS, Nauduri D, Anders MW: Targeting antioxidants to mitochondria: a new therapeutic direction. Biochim Biophys Acta 2006, 1762: 256-265.CrossRefPubMed
54.
Wheeler MD, Nakagami M, Bradford BU, Uesugi T, Mason RP, Connor HD, Dikalova A, Kadiiska M, Thurman RG: Overexpression of manganese superoxide dismutase prevents alcohol-induced liver injury in the rat. J Biol Chem 2001, 276: 36664-36672. 10.1074/jbc.M105352200CrossRefPubMed
55.
Wheeler MD, Katuna M, Smutney OM, Froh M, Dikalova A, Mason RP, Samulski RJ, Thurman RG: Comparison of the effect of adenoviral delivery of three superoxide dismutase genes against hepatic ischemia-reperfusion injury. Hum Gene Ther 2001, 12: 2167-2177. 10.1089/10430340152710513CrossRefPubMed
56.
Spasojević I, Chen Y, Noel TJ, Yu Y, Cole MP, Zhang L, Zhao Y, St Clair DK, Batinić-Haberle I: Mn porphyrin-based superoxide dismutase (SOD) mimic, MnIIITE-2-PyP5+, targets mouse heart mitochondria. Free Radic Biol Med 2007, 42: 1193-1200. 10.1016/j.freeradbiomed.2007.01.019PubMedCentralCrossRefPubMed
57.
Lowes DA, Almawash AM, Webster NR, Galley HF: Role of melatonin and indole-derivatives on endothelial cells in an in vitro model of sepsis [abstract]. Br J Anaesth 2010, 104: 525P.
58.
Packer L, Witt EH, Tritschler HJ: Alpha-lipoic acid as a biological antioxidant. Free Radic Biol Med 1995, 19: 227-250. 10.1016/0891-5849(95)00017-RCrossRefPubMed
59.
Ripcke J, Zarse K, Ristow M, Birringer M: Small-molecule targeting of the mitochondrial compartment with an endogenously cleaved reversible tag. Chembiochem 2009, 10: 1689-1696. 10.1002/cbic.200900159CrossRefPubMed
60.
Roser KS, Brookes PS, Wojtovich AP, Olson LP, Shojaie J, Parton RL, Anders MW: Mitochondrial biotransformation of omega-(phenoxy)alkanoic acids, 3-(phenoxy)acrylic acids, and omega-(1-methyl-1H-imidazol-2-ylthio) alkanoic acids: a prodrug strategy for targeting cytoprotective antioxidants to mitochondria. Bioorg Med Chem 2010, 18: 1441-1448. 10.1016/j.bmc.2010.01.019PubMedCentralCrossRefPubMed
61.
Lowes DA, Thottakam BM, Webster NR, Murphy MP, Galley HF: The mitochondria-targeted antioxidant MitoQ protects against organ damage in a lipopolysaccharide-peptidoglycan model of sepsis. Free Radic Biol Med 2008, 45: 1559-1565. 10.1016/j.freeradbiomed.2008.09.003CrossRefPubMed
62.
Minter BE, Lowes DA, Webster NR, Galley HF: Mitochondrial targeted vitamin E in an endothelial model of sepsis [abstract]. Br J Anaesth 2010, 104: 525-526P.
63.
Supinski GS, Murphy MP, Callahan LA: MitoQ administration prevents endotoxin-induced cardiac dysfunction. Am J Physiol Regul Integr Comp Physiol 2009, 297: R1095-R1102.PubMedCentralCrossRefPubMed
64.
Escames G, López LC, Ortiz F, López A, García JA, Ros E, Acuña-Castroviejo D: Attenuation of cardiac mitochondrial dysfunction by melatonin in septic mice. FEBS J 2007, 274: 2135-2147. 10.1111/j.1742-4658.2007.05755.xCrossRefPubMed
65.
Escames G, López LC, Tapias V, Utrilla P, Reiter RJ, Hitos AB, León J, Rodríguez MI, Acuña-Castroviejo D: Melatonin counteracts inducible mitochondrial nitric oxide synthase-dependent mitochondrial dysfunction in skeletal muscle of septic mice. J Pineal Res 2006, 40: 71-78. 10.1111/j.1600-079X.2005.00281.xCrossRefPubMed
66.
Vanasco V, Cimolai MC, Pablo Evelson P, Silvia Alvarez S: The oxidative stress and the mitochondrial dysfunction caused by endotoxemia are prevented by α-lipoic acid. Free Rad Res 2008, 42: 815-823. 10.1080/10715760802438709CrossRef
67.
Pandit JJ, Handy JM: Science, Anaesthesia and animal studies. What is 'evidence'? Anaesthesia 2010, 65: 223-226. 10.1111/j.1365-2044.2009.06230.xCrossRefPubMed
68.
Fink MP: Animal models of sepsis and its complications. Kidney Int 2008, 74: 991-993. 10.1038/ki.2008.442CrossRefPubMed
69.
Dyson A, Singer M: Animal models of sepsis: why does preclinical efficacy fail to translate to the clinical setting? Crit Care Med 2009, 37: S30-37. 10.1097/CCM.0b013e3181922bd3CrossRefPubMed
Metadata
Title
Bench-to-bedside review: Targeting antioxidants to mitochondria in sepsis
Author
Helen F Galley
Publication date
01-08-2010
Publisher
BioMed Central
Published in
Critical Care / Issue 4/2010
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/cc9098

Other articles of this Issue 4/2010

Critical Care 4/2010 Go to the issue

Research

Time course of nitric oxide synthases, nitrosative stress, and poly(ADP ribosylation) in an ovine sepsis model

Commentary

Activated protein C in severe acute pancreatitis without sepsis? Not just yet ...

Research

The impact of delirium on the prediction of in-hospital mortality in intensive care patients

Review

Clinical review: Intra-abdominal hypertension: does it influence the physiology of prone ventilation?

Review

Bench-to-bedside review: Glucose and stress conditions in the intensive care unit

Research

Bedside quantification of dead-space fraction using routine clinical data in patients with acute lung injury: secondary analysis of two prospective trials