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Biochim Biophys Acta. 2016 Jan;1862(1):20-31. doi: 10.1016/j.bbadis.2015.09.021. Epub 2015 Oct 3.

Bcl-xL-mediated antioxidant function abrogates the disruption of mitochondrial dynamics induced by LRRK2 inhibition.

Author information

1
Grupo de Neurofarmacología, Dpto. Ciencias Médicas, Facultad de Medicina de Albacete, Universidad de Castilla-La Mancha, IDINE, Albacete, Spain; Facultad de Medicina y Odontología, Universidad Católica de Valencia ¨San Vicente Mártir, Valencia, Spain; Unidad de Neuropsicofarmacología Traslacional, Complejo Hospitalario Universitario de Albacete, Albacete, Spain.
2
Facultad de Medicina y Odontología, Universidad Católica de Valencia ¨San Vicente Mártir, Valencia, Spain.
3
Grupo de Neurofarmacología, Dpto. Ciencias Médicas, Facultad de Medicina de Albacete, Universidad de Castilla-La Mancha, IDINE, Albacete, Spain; Unidad de Neuropsicofarmacología Traslacional, Complejo Hospitalario Universitario de Albacete, Albacete, Spain.
4
Grupo de Neurofarmacología, Dpto. Ciencias Médicas, Facultad de Medicina de Albacete, Universidad de Castilla-La Mancha, IDINE, Albacete, Spain.
5
Unidad de Neuropsicofarmacología Traslacional, Complejo Hospitalario Universitario de Albacete, Albacete, Spain. Electronic address: mgalindoa@sescam.jccm.es.
6
Grupo de Neurofarmacología, Dpto. Ciencias Médicas, Facultad de Medicina de Albacete, Universidad de Castilla-La Mancha, IDINE, Albacete, Spain. Electronic address: joaquin.jordan@uclm.es.

Abstract

We have used the human neuroblastoma cell line SH-SY5Y overexpressing Bcl-xL (SH-SY5Y/Bcl-xL) to clarify the effects of this mitochondrial protein on the control of mitochondrial dynamics and the autophagic processes which occur after the inhibition of leucine-rich repeat kinase 2 (LRRK2) with GSK2578215A. In wild type (SH-SY5Y/Neo) cells, GSK2578215A (1nM) caused a disruption of mitochondrial morphology and an imbalance in intracellular reactive oxygen species (ROS) as indicated by an increase in dichlorofluorescein fluorescence and 4-hydroxynonenal. However, SH-SY5Y/Bcl-xL cells under GSK2578215A treatment, unlike the wild type, preserved a high mitochondrial membrane potential and did not exhibit apoptotical chromatins. In contrast to wild type cells, in SH-SY5Y/Bcl-xL cells, GSK2578215A did not induce mitochondrial translocation of neither dynamin related protein-1 nor the proapoptotic protein, Bax. In SH-SY5Y/Neo, but not SH-SY5Y/Bcl-xL cells, mitochondrial fragmentation elicited by GSK2578215A precedes an autophagic response. Furthermore, the overexpression of Bcl-xL protein restores the autophagic flux pathway disrupted by this inhibitor. SH-SY5Y/Neo, but not SH-SY5Y/Bcl-xL cells, responded to LRRK2 inhibition by an increase in the levels of acetylated tubulin, indicating that this was abrogated by Bcl-xL overexpression. This hyperacetylation of tubulin took place earlier than any of the above-mentioned events suggesting that it is involved in the autophagic flux interruption. Pre-treatment with tempol prevented the GSK2578215A-induced mitochondrial fragmentation, autophagy and the rise in acetylated tubulin in SH-SY5Y/Neo cells. Thus, these data support the notion that ROS act as a second messenger connexion between LRRK2 inhibition and these deleterious responses, which are markedly alleviated by the Bcl-xL-mediated ROS generation blockade.

KEYWORDS:

Acetylated tubulin; DRP-1; LRRK2; Mitocondrial fission; Oxidative stress; Parkinson

PMID:
26435084
DOI:
10.1016/j.bbadis.2015.09.021
[Indexed for MEDLINE]
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