title: Features of idebenone and related short-chain quinones that rescue ATP levels under conditions of impaired mitochondrial complex I.
abstract: Short-chain quinones have been investigated as therapeutic molecules due to their ability to modulate cellular redox reactions, mitochondrial electron transfer and oxidative stress, which are pathologically altered in many mitochondrial and neuromuscular disorders. Recently, we and others described that certain short-chain quinones are able to bypass a deficiency in complex I by shuttling electrons directly from the cytoplasm to complex III of the mitochondrial respiratory chain to produce ATP. Although this energy rescue activity is highly interesting for the therapy of disorders associated with complex I dysfunction, no structure-activity-relationship has been reported for short-chain quinones so far. Using a panel of 70 quinones, we observed that the capacity for this cellular energy rescue as well as their effect on lipid peroxidation was influenced more by the physicochemical properties (in particular logD) of the whole molecule than the quinone moiety itself. Thus, the observed correlations allow us to explain the differential biological activities and therapeutic potential of short-chain quinones for the therapy of disorders associated with mitochondrial complex I dysfunction and/or oxidative stress.
authors.affiliation: Santhera Pharmaceuticals, Liestal, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Erb
authors.forename: Barbara
authors.initials: B
authors.lastname: Hoffmann-Enger
authors.forename: Holger
authors.initials: H
authors.lastname: Deppe
authors.forename: Michael
authors.initials: M
authors.lastname: Soeberdt
authors.forename: Roman H
authors.initials: RH
authors.lastname: Haefeli
authors.forename: Christian
authors.initials: C
authors.lastname: Rummey
authors.forename: Achim
authors.initials: A
authors.lastname: Feurer
authors.forename: Nuri
authors.initials: N
authors.lastname: Gueven
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D055598:Chemical Phenomena / Q000187:drug effects; D042967:Electron Transport Complex I / Q000172:deficiency / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D028361:Mitochondrial Diseases / Q000378:metabolism*; D051381:Rats; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D014451:Ubiquinone; D000255:Adenosine Triphosphate; D042967:Electron Transport Complex I; C036619:idebenone