The Role of Mitochondrial Dysfunction in Sepsis-induced Multi-organ Failure

Overview

Journal Virulence

Specialty Microbiology

Date 2013 Nov 5

PMID 24185508

Citations 249

Authors

Mervyn Singer

Affiliations

Soon will be listed here.

Abstract

An important role for bioenergetic dysfunction is increasingly emerging to potentially explain the paradox of clinical and biochemical organ failure in sepsis yet minimal cell death, maintained tissue oxygenation and recovery in survivors. Associations are well-recognized between the degree of mitochondrial dysfunction and outcomes. While this does not confirm cause-and-effect, it does nevertheless suggest a new route for therapeutic intervention focused on either mitochondrial protection or acceleration of the recovery process through stimulation of mitochondrial biogenesis (new protein turnover). This is particularly pertinent in light of the multiple trial failures related to immunomodulatory therapies. This overview will provide insights into mitochondrial biology, the relevance to sepsis, and therapeutic opportunities that possibly emerge.

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References

Calvano S, Xiao W, Richards D, Felciano R, Baker H, Cho R . A network-based analysis of systemic inflammation in humans. Nature. 2005; 437(7061):1032-7. DOI: 10.1038/nature03985. View

Liesa M, Palacin M, Zorzano A . Mitochondrial dynamics in mammalian health and disease. Physiol Rev. 2009; 89(3):799-845. DOI: 10.1152/physrev.00030.2008. View

Bernard S, Gray T, Buist M, Jones B, Silvester W, Gutteridge G . Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002; 346(8):557-63. DOI: 10.1056/NEJMoa003289. View

Levy B, Gibot S, Franck P, Cravoisy A, Bollaert P . Relation between muscle Na+K+ ATPase activity and raised lactate concentrations in septic shock: a prospective study. Lancet. 2005; 365(9462):871-5. DOI: 10.1016/S0140-6736(05)71045-X. View

Camici P, Prasad S, Rimoldi O . Stunning, hibernation, and assessment of myocardial viability. Circulation. 2008; 117(1):103-14. DOI: 10.1161/CIRCULATIONAHA.107.702993. View

Lancel S, Hassoun S, Favory R, Decoster B, Motterlini R, Neviere R . Carbon monoxide rescues mice from lethal sepsis by supporting mitochondrial energetic metabolism and activating mitochondrial biogenesis. J Pharmacol Exp Ther. 2009; 329(2):641-8. DOI: 10.1124/jpet.108.148049. View

Stidwill R, Rosser D, Singer M . Cardiorespiratory, tissue oxygen and hepatic NADH responses to graded hypoxia. Intensive Care Med. 1999; 24(11):1209-16. DOI: 10.1007/s001340050746. View

Landry D, Oliver J . The pathogenesis of vasodilatory shock. N Engl J Med. 2001; 345(8):588-95. DOI: 10.1056/NEJMra002709. View

Jackson J, Girard T, Gordon S, Thompson J, Shintani A, Thomason J . Long-term cognitive and psychological outcomes in the awakening and breathing controlled trial. Am J Respir Crit Care Med. 2010; 182(2):183-91. PMC: 2913233. DOI: 10.1164/rccm.200903-0442OC. View

10.

Thomas R, Khan S, Portell F, Smigrodzki R, Bennett Jr J . Recombinant human mitochondrial transcription factor A stimulates mitochondrial biogenesis and ATP synthesis, improves motor function after MPTP, reduces oxidative stress and increases survival after endotoxin. Mitochondrion. 2010; 11(1):108-18. PMC: 3005536. DOI: 10.1016/j.mito.2010.08.004. View

11.

Iwashyna T, Wesley Ely E, Smith D, Langa K . Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 2010; 304(16):1787-94. PMC: 3345288. DOI: 10.1001/jama.2010.1553. View

12.

Dixon B . The role of microvascular thrombosis in sepsis. Anaesth Intensive Care. 2004; 32(5):619-29. DOI: 10.1177/0310057X0403200502. View

13.

Tokuda K, Kida K, Marutani E, Crimi E, Bougaki M, Khatri A . Inhaled hydrogen sulfide prevents endotoxin-induced systemic inflammation and improves survival by altering sulfide metabolism in mice. Antioxid Redox Signal. 2012; 17(1):11-21. PMC: 3342565. DOI: 10.1089/ars.2011.4363. View

14.

Lowes D, Webster N, Murphy M, Galley H . Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis. Br J Anaesth. 2013; 110(3):472-80. PMC: 3570068. DOI: 10.1093/bja/aes577. View

15.

MacGarvey N, Suliman H, Bartz R, Fu P, Withers C, Welty-Wolf K . Activation of mitochondrial biogenesis by heme oxygenase-1-mediated NF-E2-related factor-2 induction rescues mice from lethal Staphylococcus aureus sepsis. Am J Respir Crit Care Med. 2012; 185(8):851-61. PMC: 3360573. DOI: 10.1164/rccm.201106-1152OC. View

16.

Piantadosi C, Withers C, Bartz R, MacGarvey N, Fu P, Sweeney T . Heme oxygenase-1 couples activation of mitochondrial biogenesis to anti-inflammatory cytokine expression. J Biol Chem. 2011; 286(18):16374-85. PMC: 3091243. DOI: 10.1074/jbc.M110.207738. View

17.

Nisoli E, Clementi E, Paolucci C, Cozzi V, Tonello C, Sciorati C . Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide. Science. 2003; 299(5608):896-9. DOI: 10.1126/science.1079368. View

18.

Abraham E, Singer M . Mechanisms of sepsis-induced organ dysfunction. Crit Care Med. 2007; 35(10):2408-16. DOI: 10.1097/01.ccm.0000282072.56245.91. View

19.

Brealey D, Brand M, Hargreaves I, Heales S, Land J, Smolenski R . Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet. 2002; 360(9328):219-23. DOI: 10.1016/S0140-6736(02)09459-X. View

20.

Kreymann G, Grosser S, Buggisch P, Gottschall C, Matthaei S, Greten H . Oxygen consumption and resting metabolic rate in sepsis, sepsis syndrome, and septic shock. Crit Care Med. 1993; 21(7):1012-9. DOI: 10.1097/00003246-199307000-00015. View