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Characterization of mitophagy in the 6-hydoxydopamine Parkinson’s disease model.

Toxicological Sciences {focus_keyword} Characterization of mitophagy in the 6-hydoxydopamine Parkinson's disease model. Toxicological SciencesToxicol Sci. 2012 Oct;129(2):411-20.

Characterization of mitophagy in the 6-hydoxydopamine Parkinson’s disease model.

Solesio ME1, Saez-Atienzar S, Jordán J, Galindo MF.

1Unidad de Neuropsicofarmacología Traslacional, Complejo Hospitalario Universitario de Albacete, Albacete, Spain.


In the present study, the activation of autophagy and its interaction with the mitochondrial fission machinery was investigated in an experimental model of Parkinson’s disease. The addition of 50µM 6-hydroxydopamine (6-OHDA) to the dopaminergic cell line SH-SY5Y profoundly stimulated formation of autophagosomes within 12h. Under these conditions, mitochondrial fission was also activated in a sustained manner, but this occurred at earlier time points (after 3h). Upon 6-OHDA treatment, dynamin-related protein 1 (Drp1) transiently translocated to mitochondria, with increased levels of mitochondrial Drp1 being observed after 3 and 9h. Pharmacological inhibition of Drp1, through treatment with the mitochondrial-division inhibitor-1 (mdivi-1), resulted in the abrogation of mitochondrial fission and in a decrease of the number of autophagic cells. In addition, 6-OHDA failed to induce the expression of the proapoptotic protein Bax in total cellular extracts although it did induce its migration to mitochondria. In our model, Bax migrated later than Drp1. However, Drp1 inhibition did not block Bax migration. These results show that reactive oxygen species but not quinone derivates act as mediators of autophagy at an early stage of the process. 6-OHDA induces hydrogen peroxide production, which was placed upstream of mitochondrial fission, given that mdivi-1 did not abrogate this increase. Furthermore, the 6-OHDA-induced activation of autophagy was also suppressed by addition of the free radical scavengers TEMPOL and MnTBAP. This effect could be reproduced by the addition of hydrogen peroxide, but not with aged 6-OHDA. To our knowledge, this is the first detailed study highlighting the various mediators that are implicated in mitochondrial alterations and autophagy of cells in response to 6-OHDA

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