title: Novel mycotoxin from Acremonium exuviarum is a powerful inhibitor of the mitochondrial respiratory chain complex III.
abstract: A novel mycotoxin named acrebol, consisting of two closely similar peptaibols (1726 and 1740 Da), was isolated from an indoor strain of the mitosporic ascomycete fungus Acremonium exuviarum. This paper describes the unique mitochondrial toxicity of acrebol, not earlier described for any peptaibol. Acrebol inhibited complex III of the respiratory chain of isolated rat liver mitochondria (1 mg of protein mL(-1)) with an IC(50) of approximately 80 ng mL(-1) (50 nM) after a short preincubation, and 350 ng mL(-1) caused immediate and complete inhibition. Acrebol thus is a complex III inhibitor almost as potent as antimycin A and myxothiazol but completely different in structure. Similarly to myxothiazol but in contrast to antimycin A, acrebol decreased the level of mitochondrial superoxide anion detectable by chemiluminescent probe 3,7-dihydro-2-methyl-6-(4-methoxyphenyl)imidazol[1,2-a]pyrazine-3-one. Unlike other peptaibols, acrebol in toxic concentrations did not increase the ionic and solute permeability of membranes of isolated rat liver mitochondria, did not induce disturbance of the ionic homeostasis or the osmotic balance of mitochondria, and did not release apoptogenic proteins like cytochrome c from the intermembrane space of mitochondria. In boar spermatozoa, acrebol inhibited the respiratory chain and caused ATP depletion by activation of the oligomycin-sensitive F(0)F(1)-ATPase, which resulted in the inhibition of the progressive movement. In mouse insulinoma MIN-6 cells, whose energy supply solely depends on oxidative phosphorylation, acrebol induced necrosis-like death. The pathophysiological relevance of these findings is discussed.
authors.affiliation: Department of Applied Chemistry and Microbiology, University of Helsinki, P.O. Box 56, FIN-00014 Helsinki, Finland.
authors.forename: Alexey G
authors.initials: AG
authors.lastname: Kruglov
authors.forename: Maria A
authors.initials: MA
authors.lastname: Andersson
authors.forename: Raimo
authors.initials: R
authors.lastname: Mikkola
authors.forename: Merja
authors.initials: M
authors.lastname: Roivainen
authors.forename: Laszlo
authors.initials: L
authors.lastname: Kredics
authors.forename: Nils-Erik L
authors.initials: NE
authors.lastname: Saris
authors.forename: Mirja S
authors.initials: MS
authors.lastname: Salkinoja-Salonen
mesh_terms: D000164:Acremonium / Q000737:chemistry*; D000818:Animals; D000968:Antimycin A / Q000378:metabolism; D004579:Electron Transport / Q000187:drug effects; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors*; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D009183:Mycotoxins / Q000633:toxicity*; D054848:Peptaibols / Q000633:toxicity*; D051381:Rats
chemical_list: D009183:Mycotoxins; D054848:Peptaibols; D000968:Antimycin A; D014450:Electron Transport Complex III