title: Self-evolving oxidative stress with identifiable pre- and postmitochondrial phases in PC12 cells.
abstract: During the neurodegenerative process in several brain diseases, oxidative stress is known to play important roles in disease severity and evolution. Although early events of stress, such as increased lipid peroxidation and decreased superoxide dismutase, are known to characterize early onsets of these diseases, little is known about the events that participate in maintaining the chronic evolving phase influencing the disease progression in neurons. Here, we used differentiated PC12 cells to identify premitochondrial and postmitochondrial events occurring during the oxidative stress cascade leading to apoptosis. Our data indicate that an acute and strong oxidative impulse (500 μM H(2)O(2), 30 min) can induce, in this model, a 24-hr self-evolving stress, which advances from a premitochondrial phase characterized by lysosomes and cathepsin B and D translocations to cytosol and early mitochondrial membrane hyperpolarization. This phase lasts for about 5 hr and is followed by a postmitochondrial phase distinguished by mitochondrial membrane depolarization, reactive oxygen species increase, caspase-9 and caspase-3 activations, and apoptosis. Inhibition of cathepsins B and D suggests that cells can be protected at the premitochondrial phase of stress evolution and that new cathepsins regulators, such as glycosaminoglycans mimetics, can be considered as new therapeutic prototypes for neurodegeneration. Insofar as early oxidative stress markers have been related to the early onset of neurodegeneration, strategies protecting cells at the premitochondrial phase of oxidative stress may have important therapeutic applications.
authors.affiliation: Laboratoire CRRET, EAC CNRS 7149, Faculté des Sciences et Technologie, Université Paris Est Créteil, France.
authors.forename: Ganlin
authors.initials: G
authors.lastname: Zhang
authors.forename: Christophe
authors.initials: C
authors.lastname: Morin
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Zhu
authors.forename: Minh
authors.initials: M
authors.lastname: Bao Huynh
authors.forename: Mohand
authors.initials: M
authors.lastname: Ouidir Ouidja
authors.forename: Julia Elisa
authors.initials: JE
authors.lastname: Sepulveda-Diaz
authors.forename: Rita
authors.initials: R
authors.lastname: Raisman-Vozari
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Dulce
authors.initials: D
authors.lastname: Papy-Garcia
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002402:Cathepsin D / Q000378:metabolism; D020059:Cathepsin E / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008315:Malondialdehyde / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D016716:PC12 Cells / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D008315:Malondialdehyde; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D053148:Caspase 3; D053453:Caspase 9; D020059:Cathepsin E; D002402:Cathepsin D; D000154:Aconitate Hydratase