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Rotenone Induces the Formation of 4-Hydroxynonenal Aggresomes. Role of ROS-Mediated Tubulin Hyperacetylation and Autophagic Flux Disruption

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Abstract

Oxidative stress causes cellular damage by (i) altering protein stability, (ii) impairing organelle function, or (iii) triggering the formation of 4-HNE protein aggregates. The catabolic process known as autophagy is an antioxidant cellular response aimed to counteract these stressful conditions. Therefore, autophagy might act as a cytoprotective response by removing impaired organelles and aggregated proteins. In the present study, we sought to understand the role of autophagy in the clearance of 4-HNE protein aggregates in ARPE-19 cells under rotenone exposure. Rotenone induced an overproduction of reactive oxygen species (ROS), which led to an accumulation of 4-HNE inclusions, and an increase in the number of autophagosomes. The latter resulted from a disturbed autophagic flux rather than an activation of the autophagic synthesis pathway. In compliance with this, rotenone treatment induced an increase in LC3-II while upstream autophagy markers such as Beclin- 1, Vsp34 or Atg5-Atg12, were decreased. Rotenone reduced the autophagosome-to-lysosome fusion step by increasing tubulin acetylation levels through a ROS-mediated pathway. Proof of this is the finding that the free radical scavenger, N-acetylcysteine, restored autophagy flux and reduced rotenone-induced tubulin hyperacetylation. Indeed, this dysfunctional autophagic response exacerbates cell death triggered by rotenone, since 3-methyladenine, an autophagy inhibitor, reduced cell mortality, while rapamycin, an inductor of autophagy, caused opposite effects. In summary, we shed new light on the mechanisms involved in the autophagic responses disrupted by oxidative stress, which take place in neurodegenerative diseases such as Huntington or Parkinson diseases, and age-related macular degeneration.

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Abbreviations

3-MA:

3-methyadenine

4-HNE:

4-hydroxynonenal

ARPE-19:

Human Retinal Pigment Epithelial Cells

CQ:

chloroquine

DCF:

dichlorofluorescein

GFP:

green fluorescent protein

H2O2 :

hydrogen peroxide

LC3:

microtubule-associated protein 1A/1B light chain 3

NAC:

N-acetylcysteine

PI:

propidium iodide

RFP:

red fluorescent protein

ROS:

reactive oxygen species

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Acknowledgments

We thank Carlos Garrido for his technical help and Dr E. Knecht for providing the mRFP-GFP-LC3 vector. This work was supported by a grant from the Ministerio de Ciencia e Innovación, Spain (SAF2010-21317), funds from the Universidad Católica de Valencia to FJR, and JCCM to JJ.

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Authors and Affiliations

  1. Facultad de Medicina y Odontología, Universidad Católica de Valencia San Vicente Mártir, Valencia, Spain

    Luis Bonet-Ponce, Sara Saez-Atienzar, Javier Sancho-Pelluz, Jorge M. Barcia, Natalia Martinez-Gil & Francisco J. Romero

  2. Unidad de Neuropsicofarmacología Traslacional, Complejo Hospitalario Universitario de Albacete, Albacete, Spain

    Sara Saez-Atienzar & Maria F. Galindo

  3. Grupo de Neurofarmacología, Dpto. Ciencias Médicas. Facultad de Medicina de Albacete, IDINE, Universidad de Castilla-La Mancha, Albacete, Spain

    Sara Saez-Atienzar, Carmen da Casa, Eduardo Nava & Joaquín Jordan

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  1. Luis Bonet-Ponce
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Correspondence to Maria F. Galindo.

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Bonet-Ponce, L., Saez-Atienzar, S., da Casa, C. et al. Rotenone Induces the Formation of 4-Hydroxynonenal Aggresomes. Role of ROS-Mediated Tubulin Hyperacetylation and Autophagic Flux Disruption. Mol Neurobiol 53, 6194–6208 (2016). https://doi.org/10.1007/s12035-015-9509-3

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