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Compromising mitochondrial function with the antiretroviral drug efavirenz induces cell survival-promoting autophagy

Authors

  • Nadezda Apostolova,

    Corresponding author
    1. Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
    2. CIBERehd, Valencia, Spain
    • Facultad de Medicina, Universidad de Valencia, Avda. Blasco Ibáñez n.15-17, 46010 Valencia, Spain
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    • fax: (+34) 963983879

  • Leysa J. Gomez-Sucerquia,

    1. Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
    2. Hospital Universitario Dr. Peset, Valencia, Spain
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  • Anna Gortat,

    1. Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
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  • Ana Blas-Garcia,

    1. Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
    2. Hospital Universitario Dr. Peset, Valencia, Spain
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  • Juan V. Esplugues

    1. Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
    2. CIBERehd, Valencia, Spain
    3. Hospital Universitario Dr. Peset, Valencia, Spain
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  • Potential conflict of interest: Nothing to report.

  • Supported by grants PI081325 and CIBER CD06/04/0071 (Ministerio de Sanidad y Consumo, Spain), PROMETEO/2010/060 and ACOMP/2010/207 (GeneralitatValenciana, Spain) and an unrestricted grant from Abbott Laboratories.

Abstract

Hepatotoxicity is a very common side effect associated with the pharmacological treatment of human immunodeficiency virus (HIV) infection and its pathogenesis is poorly understood. Efavirenz (EFV) is the most widely used nonnucleoside reverse transcriptase inhibitor administered for the control of HIV and some of its toxic effects in hepatic cells have been recently shown to display features of mitochondrial dysfunction. Here we studied the activation of autophagy and, in particular, mitophagy, the main mitochondrial turnover mechanism, in human hepatic cells treated with clinically relevant concentrations of this drug. EFV-treated cells had altered mitochondria, characterized by a relative increase in mitochondrial mass and defective morphology. This was followed by induction of autophagy as shown by the presence of autophagic vacuoles and the presence of the specific autophagic marker proteins microtubule-associated protein 1A/1B light chain 3 and Beclin-1. Importantly, whereas moderate levels of EFV activated autophagy, higher concentrations led to blockage in the autophagic flux, a condition that promotes “autophagic stress” and produces severe cellular damage. Finally, pharmacological inhibition of autophagy exacerbated the deleterious effect of EFV on cell survival/proliferation promoting apoptosis, which suggests that autophagy acts as an adaptive mechanism of cell survival. Conclusion: Clinical concentrations of EFV induce autophagy and, in particular, mitophagy in hepatic cells. Activation of this process promotes cell survival, but exceeding a certain threshold of mitochondrial dysfunction is associated with an autophagic overload or stress. This effect could be involved in the EFV-associated hepatotoxicity and may constitute a new mechanism implicated in the genesis of drug-induced liver damage. (HEPATOLOGY 2011;)

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