Enhanced mitochondrial radical production in patients which rheumatoid arthritis correlates with elevated levels of tumor necrosis factor alpha in plasma.
Mitochondrial dysfunction contributes to cell damage in a number of human diseases. One significant mechanism by which mitochondria damage cells is by producing reactive oxygen species from the respiratory chain. In this study we measured the production of reactive oxygen species by leukocyte mitochondria in blood from rheumatoid arthritis patients. To do this we used the chemiluminescence of lucigenin, which is accumulated by mitochondria within cells and reacts with superoxide to form a chemiluminescent product. By using specific inhibitors we could distinguish between the production of reactive oxygen species by mitochondria and by NADPH oxidase. There was a five-fold increase in mitochondrial reactive oxygen species production in whole blood and monocytes from patients with rheumatoid arthritis, when compared to healthy subjects or patients with non-rheumatic diseases. There was no increases in mitochondrial reactive oxygen species production by neutrophils from rheumatoid arthritis patients. The enhanced mitochondrial radical production in rheumatoid arthritis patients correlated significantly with increased levels of tumor necrosis factor alpha in plasma (p < 0.0001). As tumor necrosis factor alpha is known to increase mitochondrial reactive oxygen species production the elevated mitochondrial radical formation seen in rheumatoid arthritis patients may be due to activation of the mitochondrial radical production. These data suggest that elevated mitochondrial oxidative stress contributes to the pathology of rheumatoid arthritis.
Miesel
R
R
University of Otago, Department of Biochemistry, Dunedin, New Zealand. rmiesel@sanger.otago.ac.nz
Murphy
M P
MP
Kröger
H
H
D000166:Acridines; D000968:Antimycin A / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000097:blood*; D005609:Free Radicals; D006801:Humans; D007962:Leukocytes / Q000648:ultrastructure*; D008163:Luminescent Measurements; D008928:Mitochondria / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D009840:Oligomycins / Q000494:pharmacology; D018384:Oxidative Stress; D011190:Potassium Cyanide / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012402:Rotenone / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014475:Uncoupling Agents / Q000494:pharmacology
D000166:Acridines; D005609:Free Radicals; D009840:Oligomycins; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D014475:Uncoupling Agents; D012402:Rotenone; C033472:10,10'-dimethyl-9,9'-biacridinium; D000968:Antimycin A; D019255:NADPH Oxidases; D011190:Potassium Cyanide