title: A biophysical approach to menadione membrane interactions: relevance for menadione-induced mitochondria dysfunction and related deleterious/therapeutic effects.
abstract: Menadione (MEN), a polycyclic aromatic ketone, was shown to promote cell injury by imposing massive oxidative stress and has been proposed as a promising chemotherapeutic agent for the treatment of cancer diseases. The mechanisms underlying MEN-induced mitochondrial dysfunction and cell death are not yet fully understood. In this work, a systematic study was performed to unveil the effects of MEN on membrane lipid organization, using models mimicking mitochondrial membranes and native mitochondrial membranes. MEN was found to readily incorporate in membrane systems composed of a single phospholipid (phosphatidylcholine) or the lipids dioleoylphosphatidylcholine, dioleoylphosphatidylethanolamine and tetraoleoylcardiolipin at 1:1:1 molar ratio, as well as in mitochondrial membranes. Increased permeability in both membrane models, monitored by calcein release, seemed to correlate with the extent of MEN incorporation into membranes. MEN perturbed the physical properties of vesicles composed of dipalmitoylphosphatidylcholine or dipalmitoylphosphatidylethanolamine plus tetraoleoylcardiolipin (at 7:3 molar ratio), as reflected by the downshift of the lipid phase transition temperature and the emergence of a new transition peak in the mixed lipid system, detected by DSC. (31)P NMR studies revealed that MEN favored the formation of non-lamellar structures. Also, quenching studies with the fluorescent probes DPH and TMA-DPH showed that MEN distributed across the bilayer thickness in both model and native mitochondrial membranes. MEN's ability to promote alterations of membrane lipid organization was related with its reported mitochondrial toxicity and promotion of apoptosis, predictably involved in its anti-carcinogenic activity.
authors.affiliation: Department of Life Sciences, University of Coimbra, Portugal.
authors.forename: João P
authors.initials: JP
authors.lastname: Monteiro
authors.forename: André F
authors.initials: AF
authors.lastname: Martins
authors.forename: Cláudia
authors.initials: C
authors.lastname: Nunes
authors.forename: Catarina M
authors.initials: CM
authors.lastname: Morais
authors.forename: Marlene
authors.initials: M
authors.lastname: Lúcio
authors.forename: Salette
authors.initials: S
authors.lastname: Reis
authors.forename: Teresa J T
authors.initials: TJ
authors.lastname: Pinheiro
authors.forename: Carlos F G C
authors.initials: CF
authors.lastname: Geraldes
authors.forename: Paulo J
authors.initials: PJ
authors.lastname: Oliveira
authors.forename: Amália S
authors.initials: AS
authors.lastname: Jurado
mesh_terms: D001703:Biophysics; D002152:Calorimetry, Differential Scanning; D002463:Cell Membrane Permeability; D005452:Fluoresceins / Q000378:metabolism; D005453:Fluorescence; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism*; D008563:Membrane Lipids / Q000737:chemistry / Q000378:metabolism*; D008567:Membranes, Artificial; D008928:Mitochondria / Q000737:chemistry / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000737:chemistry / Q000378:metabolism*; D010714:Phosphatidylethanolamines / Q000737:chemistry / Q000378:metabolism*; D013053:Spectrophotometry; D024483:Vitamin K 3 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D005452:Fluoresceins; D008051:Lipid Bilayers; D008563:Membrane Lipids; D008567:Membranes, Artificial; D010714:Phosphatidylethanolamines; D024483:Vitamin K 3; C007740:fluorexon