title: Oxidative stress modulates mitochondrial failure and cyclophilin D function in X-linked adrenoleukodystrophy.
abstract: A common process associated with oxidative stress and severe mitochondrial impairment is the opening of the mitochondrial permeability transition pore, as described in many neurodegenerative diseases. Thus, inhibition of mitochondrial permeability transition pore opening represents a potential target for inhibiting mitochondrial-driven cell death. Among the mitochondrial permeability transition pore components, cyclophilin D is the most studied and has been found increased under pathological conditions. Here, we have used in vitro and in vivo models of X-linked adrenoleukodystrophy to investigate the relationship between the mitochondrial permeability transition pore opening and redox homeostasis. X-linked adrenoleukodystrophy is a neurodegenerative condition caused by loss of function of the peroxisomal ABCD1 transporter, in which oxidative stress plays a pivotal role. In this study, we provide evidence of impaired mitochondrial metabolism in a peroxisomal disease, as fibroblasts in patients with X-linked adrenoleukodystrophy cannot survive when forced to rely on mitochondrial energy production, i.e. on incubation in galactose. Oxidative stress induced under galactose conditions leads to mitochondrial damage in the form of mitochondrial inner membrane potential dissipation, ATP drop and necrotic cell death, together with increased levels of oxidative modifications in cyclophilin D protein. Moreover, we show increased expression levels of cyclophilin D in the affected zones of brains in patients with adrenomyeloneuropathy, in spinal cord of a mouse model of X-linked adrenoleukodystrophy (Abcd1-null mice) and in fibroblasts from patients with X-linked adrenoleukodystrophy. Notably, treatment with antioxidants rescues mitochondrial damage markers in fibroblasts from patients with X-linked adrenoleukodystrophy, including cyclophilin D oxidative modifications, and reverses cyclophilin D induction in vitro and in vivo. These findings provide mechanistic insight into the beneficial effects of antioxidants in neurodegenerative and non-neurodegenerative cyclophilin D-dependent disorders.
authors.affiliation: Neurometabolic Diseases Laboratory, Institute of Neuropathology, IDIBELL, 08908 L' Hospitalet de Llobregat, Barcelona, Catalonia, Spain.
authors.forename: Jone
authors.initials: J
authors.lastname: López-Erauskin
authors.forename: Jorge
authors.initials: J
authors.lastname: Galino
authors.forename: Patrizia
authors.initials: P
authors.lastname: Bianchi
authors.forename: Stéphane
authors.initials: S
authors.lastname: Fourcade
authors.forename: Antoni L
authors.initials: AL
authors.lastname: Andreu
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.forename: Cristina
authors.initials: C
authors.lastname: Muñoz-Pinedo
authors.forename: Aurora
authors.initials: A
authors.lastname: Pujol
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000172:deficiency; D000111:Acetylcysteine / Q000008:administration & dosage; D000255:Adenosine Triphosphate / Q000378:metabolism; D000326:Adrenoleukodystrophy / Q000178:diet therapy / Q000473:pathology*; D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019328:Buthionine Sulfoximine / Q000008:administration & dosage; D016923:Cell Death; D002843:Chromatin / Q000473:pathology; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*; D005434:Flow Cytometry; D005690:Galactose / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D018696:Neuroprotective Agents / Q000008:administration & dosage; D009842:Oligopeptides / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010539:Permeability / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D008063:Thioctic Acid / Q000008:administration & dosage; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism; D014810:Vitamin E / Q000008:administration & dosage
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D002843:Chromatin; D000081406:Peptidyl-Prolyl Isomerase F; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D009842:Oligopeptides; C000631446:PPIF protein, mouse; D017382:Reactive Oxygen Species; D014404:Tubulin; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; D014810:Vitamin E; D019328:Buthionine Sulfoximine; D008063:Thioctic Acid; D000255:Adenosine Triphosphate; D021983:Cyclophilins; D005978:Glutathione; D005947:Glucose; D000111:Acetylcysteine; D005690:Galactose