The mitochondria-targeted antioxidant MitoQ protects against organ damage in a lipopolysaccharide-peptidoglycan model of sepsis.
Sepsis is characterised by a systemic dysregulated inflammatory response and oxidative stress, often leading to organ failure and death. Development of organ dysfunction associated with sepsis is now accepted to be due at least in part to oxidative damage to mitochondria. MitoQ is an antioxidant selectively targeted to mitochondria that protects mitochondria from oxidative damage and which has been shown to decrease mitochondrial damage in animal models of oxidative stress. We hypothesised that if oxidative damage to mitochondria does play a significant role in sepsis-induced organ failure, then MitoQ should modulate inflammatory responses, reduce mitochondrial oxidative damage, and thereby ameliorate organ damage. To assess this, we investigated the effects of MitoQ in vitro in an endothelial cell model of sepsis and in vivo in a rat model of sepsis. In vitro MitoQ decreased oxidative stress and protected mitochondria from damage as indicated by a lower rate of reactive oxygen species formation (P=0.01) and by maintenance of the mitochondrial membrane potential (P<0.005). MitoQ also suppressed proinflammatory cytokine release from the cells (P<0.05) while the production of the anti-inflammatory cytokine interleukin-10 was increased by MitoQ (P<0.001). In a lipopolysaccharide-peptidoglycan rat model of the organ dysfunction that occurs during sepsis, MitoQ treatment resulted in lower levels of biochemical markers of acute liver and renal dysfunction (P<0.05), and mitochondrial membrane potential was augmented (P<0.01) in most organs. These findings suggest that the use of mitochondria-targeted antioxidants such as MitoQ may be beneficial in sepsis.
Academic Unit of Anaesthesia and Intensive Care, School of Medicine, Institute of Medical Sciences, Foresterhill, Aberdeen, UK.
Damon A
DA
Lowes
Bensita M V
BM
Thottakam
Nigel R
NR
Webster
Michael P
MP
Murphy
Helen F
HF
Galley
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002460:Cell Line; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000502:physiology; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010457:Peptidoglycan / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy* / Q000503:physiopathology; D013050:Spectrometry, Fluorescence; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology
D000975:Antioxidants; D016207:Cytokines; D008070:Lipopolysaccharides; D009943:Organophosphorus Compounds; D010457:Peptidoglycan; D017382:Reactive Oxygen Species; D016753:Interleukin-10; D014451:Ubiquinone; C429014:mitoquinone; D003404:Creatinine