title: Induction of mitochondrial destabilization and necrotic cell death by apolar mitochondria-directed SOD mimetics.
abstract: In this paper, we present evidence, for the first time, that increasing the lipophilicity of mitochondria targeting SOD mimetics reverses their cytoprotective properties, destabilizing the mitochondrial membrane system and promoting cell death. A new mitochondria-directed apolar SOD mimetic, HO-3814, was found to provoke mitochondrial swelling and loss of mitochondrial membrane potential, and these effects were not inhibited by cyclosporine A. HO-3814-induced cell death was predominantly necrotic, caspase-independent, and not affected by mitochondrial permeability transition inhibitors or cyclophilin D-suppression, inhibitors of mitogen-activated protein kinases or Akt, or various antioxidants. In contrast, Bcl-2 overexpression diminished the effects of HO-3814.
authors.affiliation: Department of Biochemistry and Medical Chemistry, University of Pecs, Hungary.
authors.forename: Aliz
authors.initials: A
authors.lastname: Szabo
authors.forename: Maria
authors.initials: M
authors.lastname: Balog
authors.forename: Laszlo
authors.initials: L
authors.lastname: Mark
authors.forename: Gergely
authors.initials: G
authors.lastname: Montsko
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Turi
authors.forename: Ferenc
authors.initials: F
authors.lastname: Gallyas
authors.forename: Balazs
authors.initials: B
authors.lastname: Sumegi
authors.forename: Tamas
authors.initials: T
authors.lastname: Kalai
authors.forename: Kalman
authors.initials: K
authors.lastname: Hideg
authors.forename: Krisztina
authors.initials: K
authors.lastname: Kovacs
mesh_terms: D000818:Animals; D016923:Cell Death; D002460:Cell Line; D016166:Free Radical Scavengers / Q000633:toxicity*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D016166:Free Radical Scavengers; D013482:Superoxide Dismutase