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Self-evolving oxidative stress with identifiable pre- and postmitochondrial phases in PC12 cells

Authors

  • Ganlin Zhang,

    1. Laboratoire CRRET, EAC CNRS 7149, Faculté des Sciences et Technologie, Université Paris Est Créteil, France
    2. Beijing Hospital of Traditional Chinese Medicine, affiliated with Capital Medical University, Beijing, People's Republic of China
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  • Christophe Morin,

    1. Laboratoire CRRET, EAC CNRS 7149, Faculté des Sciences et Technologie, Université Paris Est Créteil, France
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  • Xiaoxin Zhu,

    1. Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, People's Republic of China
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  • Minh Bao Huynh,

    1. Laboratoire CRRET, EAC CNRS 7149, Faculté des Sciences et Technologie, Université Paris Est Créteil, France
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  • Mohand Ouidir Ouidja,

    1. Laboratoire CRRET, EAC CNRS 7149, Faculté des Sciences et Technologie, Université Paris Est Créteil, France
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  • Julia Elisa Sepulveda-Diaz,

    1. Laboratoire CRRET, EAC CNRS 7149, Faculté des Sciences et Technologie, Université Paris Est Créteil, France
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  • Rita Raisman-Vozari,

    1. INSERM UMR-S 975, UPMC, CRICM, Experimental Therapeutics of Neurodegeneration, Paris, France
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  • Ping Li,

    Corresponding author
    1. Department of Pathophysiology, Beijing Institute of Chinese Medicine, Beijing, People's Republic of China
    • Department of Pathophysiology, Beijing Institute of Chinese Medicine, 100010, Beijing, PR China
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  • Dulce Papy-Garcia

    Corresponding author
    1. Laboratoire CRRET, EAC CNRS 7149, Faculté des Sciences et Technologie, Université Paris Est Créteil, France
    • Laboratoire CRRET, Université Paris Est Créteil, 61 Av. du Général de Gaulle, 94010 Créteil cedex, France
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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 H2O2, 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. © 2012 Wiley Periodicals, Inc.

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