Kinetic and protective role of autophagy in manganese-exposed BV-2 cells.

Autor: Porte Alcon S; CONICET- Universidad de Buenos Aires. Instituto de Química Biológica Ciencias Exactas y Naturales (IQUIBICEN). Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, Laboratorio de Disfunción Celular en Enfermedades Neurodegenerativas y Nanomedicina. Ciudad Autónoma de Buenos Aires, Argentina. Electronic address: sportealcon@qb.fcen.uba.ar., Gorojod RM; CONICET- Universidad de Buenos Aires. Instituto de Química Biológica Ciencias Exactas y Naturales (IQUIBICEN). Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, Laboratorio de Disfunción Celular en Enfermedades Neurodegenerativas y Nanomedicina. Ciudad Autónoma de Buenos Aires, Argentina. Electronic address: rgorojod@qb.fcen.uba.ar., Kotler ML; CONICET- Universidad de Buenos Aires. Instituto de Química Biológica Ciencias Exactas y Naturales (IQUIBICEN). Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, Laboratorio de Disfunción Celular en Enfermedades Neurodegenerativas y Nanomedicina. Ciudad Autónoma de Buenos Aires, Argentina. Electronic address: kotler@qb.fcen.uba.ar.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Molecular cell research [Biochim Biophys Acta Mol Cell Res] 2020 Oct; Vol. 1867 (10), pp. 118787. Date of Electronic Publication: 2020 Jun 24.
DOI: 10.1016/j.bbamcr.2020.118787
Abstrakt: Manganese (Mn) plays an important role in many physiological processes. Nevertheless, Mn accumulation in the brain can cause a parkinsonian-like syndrome known as manganism. Unfortunately, the therapeutic options for this disease are scarce and of limited efficacy. For this reason, a great effort is being made to understand the cellular and molecular mechanisms involved in Mn toxicity in neuronal and glial cells. Even though evidence indicates that Mn activates autophagy in microglia, the consequences of this activation in cell death remain unknown. In this study, we demonstrated a key role of reactive oxygen species in Mn-induced damage in microglial cells. These species generated by Mn 2+ induce lysosomal alterations, LMP, cathepsins release and cell death. Besides, we described for the first time the kinetic of Mn 2+ -induced autophagy in BV-2 microglial cells and its relevance to cell fate. We found that Mn promotes a time-dependent increase in LC3-II and p62 expression levels, suggesting autophagy activation. Possibly, cells trigger autophagy to neutralize the risks associated with lysosomal rupture. In addition, pre-treatment with both Rapamycin and Melatonin enhanced autophagy and retarded Mn 2+ cytotoxicity. In summary, our results demonstrated that, despite the damage inflicted on a subset of lysosomes, the autophagic pathway plays a protective role in Mn-induced microglial cell death. We propose that 2 h Mn 2+ exposure will not induce disturbances in the autophagic flux. However, as time passes, the accumulated damage inside the cell could trigger a dysfunction of this mechanism. These findings may represent a valuable contribution to future research concerning manganism therapies.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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