Leukotoxin, 9,10-epoxy-12-octadecenoate inhibits mitochondrial respiration of isolated perfused rat lung.
To investigate how mitochondrial function was affected in leukotoxin (Lx)-,9,10-epoxy-12-octadecenoate-induced lung injury, lung mitochondria were extracted from isolated perfused rat lung with or without Lx-induced edematous injury. In the lung treated with 30 mumol of Lx, the mitochondrial respiration rate in states 3 and 4 significantly decreased (without mitochondrial uncoupling) concomitantly with increased release of lactate dehydrogenase (LDH), a parameter for cellular damage, into the perfusate and decreased ATP content in the lung tissue compared with those of untreated lung. Moreover, 30 mumol of Lx resulted in significant inhibition of cytochrome-c oxidase activity (vs. vehicle control). In contrast, lower doses of Lx (10 mumol) caused lung edema and cellular damage without evidence for mitochondrial dysfunction. We also examined cellular and mitochondrial damage in hydrostatic lung edema. Such edema showed neither suppressed mitochondrial respiration nor elevated LDH activity in perfusate, although lung wet weight increased as much as it did after 30 mumol Lx treatment. Our results suggest that the ex vivo mitochondrial dysfunction is one of the secondary (vs. initial augmented permeability) but specific manifestations of toxicity of Lx, and together with the previous reports, the ex vivo damaging effect of Lx against mitochondria may be ascribed not to its direct action on mitochondria but to Lx-derived cellular mechanism(s).
Sakai
T
T
Third Department of Internal Medicine, Fukui Medical School, Japan.
Ishizaki
T
T
Ohnishi
T
T
Sasaki
F
F
Ameshima
S
S
Nakai
T
T
Miyabo
S
S
Matsukawa
S
S
Hayakawa
M
M
Ozawa
T
T
D000227:Adenine Nucleotides / Q000378:metabolism; D000818:Animals; D003603:Cytotoxins / Q000494:pharmacology; D005098:Exotoxins / Q000494:pharmacology*; D066298:In Vitro Techniques; D008041:Linoleic Acids / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D009929:Organ Size; D010101:Oxygen Consumption / Q000187:drug effects; D010477:Perfusion; D011312:Pressure; D011651:Pulmonary Artery / Q000187:drug effects; D012123:Pulmonary Ventilation; D051381:Rats; D017207:Rats, Sprague-Dawley
D000227:Adenine Nucleotides; D003603:Cytotoxins; D005098:Exotoxins; D008041:Linoleic Acids; C018579:leukotoxin; C051208:9,10-epoxy-12-octadecenoic acid