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

KOTLER ML; PORTE ALCON S; GOROJOD RM

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2020 vol. 1867

0167-4889

Manganese (Mn) plays an important role in many physiological processes. Nevertheless, Mn accumulation in thebrain can cause a parkinsonian-like syndrome known as manganism. Unfortunately, the therapeutic options forthis disease are scarce and of limited efficacy. For this reason, a great effort is being made to understand thecellular and molecular mechanisms involved in Mn toxicity in neuronal and glial cells. Even though evidenceindicates that Mn activates autophagy in microglia, the consequences of this activation in cell death remainunknown. In this study, we demonstrated a key role of reactive oxygen species in Mn-induced damage in microglialcells. These species generated by Mn2+ induce lysosomal alterations, LMP, cathepsins release and celldeath. Besides, we described for the first time the kinetic of Mn2+-induced autophagy in BV-2 microglial cellsand its relevance to cell fate. We found that Mn promotes a time-dependent increase in LC3-II and p62 expressionlevels, suggesting autophagy activation. Possibly, cells trigger autophagy to neutralize the risks associated withlysosomal rupture. In addition, pre-treatment with both Rapamycin and Melatonin enhanced autophagy andretarded Mn2+ cytotoxicity. In summary, our results demonstrated that, despite the damage inflicted on a subsetof lysosomes, the autophagic pathway plays a protective role in Mn-induced microglial cell death. We proposethat 2 h Mn2+ exposure will not induce disturbances in the autophagic flux. However, as time passes, theaccumulated damage inside the cell could trigger a dysfunction of this mechanism. These findings may representa valuable contribution to future research concerning manganism therapies.