The autophagic- lysosomal pathway determines the fate of glial cells under manganese- induced oxidative stress conditions
Manganese (Mn) overexposure is frequently associated with the development of a neurodegenerative disorder known as Manganism. The Mn-mediated generation of reactive oxygen species (ROS) promotes cellular damage, finally leading to apoptotic cell death in rat astrocytoma C6 cells. In this scenario, t...
Guardado en:
| Publicado: |
2015
|
|---|---|
| Materias: | |
| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_08915849_v87_n_p237_Gorojod http://hdl.handle.net/20.500.12110/paper_08915849_v87_n_p237_Gorojod |
| Aporte de: |
| id |
paper:paper_08915849_v87_n_p237_Gorojod |
|---|---|
| record_format |
dspace |
| spelling |
paper:paper_08915849_v87_n_p237_Gorojod2023-06-08T15:47:13Z The autophagic- lysosomal pathway determines the fate of glial cells under manganese- induced oxidative stress conditions Acidic vesicular organelles Autophagy Cathepsin Glial cells Lysosomal cell death Manganese Mitophagy Reactive oxygen species bafilomycin A1 beclin 1 cathepsin B cathepsin B inhibitor dansylcadaverine manganese protein bcl 2 protein bcl x LC3 protein, rat manganese microtubule associated protein reactive oxygen metabolite animal cell Article astrocyte autophagy cell death cell permeabilization cell viability cytotoxicity glia cell lysosome lysosome membrane mitophagy mouse nonhuman oxidative stress priority journal animal apoptosis astrocytoma autophagy biosynthesis cell survival drug effects gene expression regulation genetics glia lysosome metabolism pathology rat tumor cell line Rattus Animals Apoptosis Astrocytoma Autophagy Cell Line, Tumor Cell Survival Gene Expression Regulation Lysosomes Manganese Metabolic Networks and Pathways Microtubule-Associated Proteins Neuroglia Oxidative Stress Rats Reactive Oxygen Species Manganese (Mn) overexposure is frequently associated with the development of a neurodegenerative disorder known as Manganism. The Mn-mediated generation of reactive oxygen species (ROS) promotes cellular damage, finally leading to apoptotic cell death in rat astrocytoma C6 cells. In this scenario, the autophagic pathway could play an important role in preventing cytotoxicity. In the present study, we found that Mn induced an increase in the amount and total volume of acidic vesicular organelles (AVOs), a process usually related to the activation of the autophagic pathway. Particularly, the generation of enlarged AVOs was a ROS- dependent event. In this report we demonstrated for the first time that Mn induces autophagy in glial cells. This conclusion emerged from the results obtained employing a battery of autophagy markers: a) the increase in LC3-II expression levels, b) the formation of autophagic vesicles labeled with monodansylcadaverine (MDC) or LC3 and, c) the increase in Beclin 1/ Bcl-2 and Beclin 1/ Bcl-XL ratio. Autophagy inhibition employing 3-MA and mAtg5K130R resulted in decreased cell viability indicating that this event plays a protective role in Mn- induced cell death. In addition, mitophagy was demonstrated by an increase in LC3 and TOM-20 colocalization. On the other hand, we proposed the occurrence of lysosomal membrane permeabilization (LMP) based in the fact that cathepsins B and D activities are essential for cell death. Both cathepsin B inhibitor (Ca-074 Me) or cathepsin D inhibitor (Pepstatin A) completely prevented Mn- induced cytotoxicity. In addition, low dose of Bafilomycin A1 showed a similar effect, a finding that adds evidence about the lysosomal role in Mn cytotoxicity. Finally, in vivo experiments demonstrated that Mn induces injury and alters LC3 expression levels in rat striatal astrocytes. In summary, our results demonstrated that autophagy is activated to counteract the harmful effect caused by Mn. These data is valuable to be considered in future research concerning Manganism therapies. © 2015 Published by Elsevier Inc. 2015 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_08915849_v87_n_p237_Gorojod http://hdl.handle.net/20.500.12110/paper_08915849_v87_n_p237_Gorojod |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Acidic vesicular organelles Autophagy Cathepsin Glial cells Lysosomal cell death Manganese Mitophagy Reactive oxygen species bafilomycin A1 beclin 1 cathepsin B cathepsin B inhibitor dansylcadaverine manganese protein bcl 2 protein bcl x LC3 protein, rat manganese microtubule associated protein reactive oxygen metabolite animal cell Article astrocyte autophagy cell death cell permeabilization cell viability cytotoxicity glia cell lysosome lysosome membrane mitophagy mouse nonhuman oxidative stress priority journal animal apoptosis astrocytoma autophagy biosynthesis cell survival drug effects gene expression regulation genetics glia lysosome metabolism pathology rat tumor cell line Rattus Animals Apoptosis Astrocytoma Autophagy Cell Line, Tumor Cell Survival Gene Expression Regulation Lysosomes Manganese Metabolic Networks and Pathways Microtubule-Associated Proteins Neuroglia Oxidative Stress Rats Reactive Oxygen Species |
| spellingShingle |
Acidic vesicular organelles Autophagy Cathepsin Glial cells Lysosomal cell death Manganese Mitophagy Reactive oxygen species bafilomycin A1 beclin 1 cathepsin B cathepsin B inhibitor dansylcadaverine manganese protein bcl 2 protein bcl x LC3 protein, rat manganese microtubule associated protein reactive oxygen metabolite animal cell Article astrocyte autophagy cell death cell permeabilization cell viability cytotoxicity glia cell lysosome lysosome membrane mitophagy mouse nonhuman oxidative stress priority journal animal apoptosis astrocytoma autophagy biosynthesis cell survival drug effects gene expression regulation genetics glia lysosome metabolism pathology rat tumor cell line Rattus Animals Apoptosis Astrocytoma Autophagy Cell Line, Tumor Cell Survival Gene Expression Regulation Lysosomes Manganese Metabolic Networks and Pathways Microtubule-Associated Proteins Neuroglia Oxidative Stress Rats Reactive Oxygen Species The autophagic- lysosomal pathway determines the fate of glial cells under manganese- induced oxidative stress conditions |
| topic_facet |
Acidic vesicular organelles Autophagy Cathepsin Glial cells Lysosomal cell death Manganese Mitophagy Reactive oxygen species bafilomycin A1 beclin 1 cathepsin B cathepsin B inhibitor dansylcadaverine manganese protein bcl 2 protein bcl x LC3 protein, rat manganese microtubule associated protein reactive oxygen metabolite animal cell Article astrocyte autophagy cell death cell permeabilization cell viability cytotoxicity glia cell lysosome lysosome membrane mitophagy mouse nonhuman oxidative stress priority journal animal apoptosis astrocytoma autophagy biosynthesis cell survival drug effects gene expression regulation genetics glia lysosome metabolism pathology rat tumor cell line Rattus Animals Apoptosis Astrocytoma Autophagy Cell Line, Tumor Cell Survival Gene Expression Regulation Lysosomes Manganese Metabolic Networks and Pathways Microtubule-Associated Proteins Neuroglia Oxidative Stress Rats Reactive Oxygen Species |
| description |
Manganese (Mn) overexposure is frequently associated with the development of a neurodegenerative disorder known as Manganism. The Mn-mediated generation of reactive oxygen species (ROS) promotes cellular damage, finally leading to apoptotic cell death in rat astrocytoma C6 cells. In this scenario, the autophagic pathway could play an important role in preventing cytotoxicity. In the present study, we found that Mn induced an increase in the amount and total volume of acidic vesicular organelles (AVOs), a process usually related to the activation of the autophagic pathway. Particularly, the generation of enlarged AVOs was a ROS- dependent event. In this report we demonstrated for the first time that Mn induces autophagy in glial cells. This conclusion emerged from the results obtained employing a battery of autophagy markers: a) the increase in LC3-II expression levels, b) the formation of autophagic vesicles labeled with monodansylcadaverine (MDC) or LC3 and, c) the increase in Beclin 1/ Bcl-2 and Beclin 1/ Bcl-XL ratio. Autophagy inhibition employing 3-MA and mAtg5K130R resulted in decreased cell viability indicating that this event plays a protective role in Mn- induced cell death. In addition, mitophagy was demonstrated by an increase in LC3 and TOM-20 colocalization. On the other hand, we proposed the occurrence of lysosomal membrane permeabilization (LMP) based in the fact that cathepsins B and D activities are essential for cell death. Both cathepsin B inhibitor (Ca-074 Me) or cathepsin D inhibitor (Pepstatin A) completely prevented Mn- induced cytotoxicity. In addition, low dose of Bafilomycin A1 showed a similar effect, a finding that adds evidence about the lysosomal role in Mn cytotoxicity. Finally, in vivo experiments demonstrated that Mn induces injury and alters LC3 expression levels in rat striatal astrocytes. In summary, our results demonstrated that autophagy is activated to counteract the harmful effect caused by Mn. These data is valuable to be considered in future research concerning Manganism therapies. © 2015 Published by Elsevier Inc. |
| title |
The autophagic- lysosomal pathway determines the fate of glial cells under manganese- induced oxidative stress conditions |
| title_short |
The autophagic- lysosomal pathway determines the fate of glial cells under manganese- induced oxidative stress conditions |
| title_full |
The autophagic- lysosomal pathway determines the fate of glial cells under manganese- induced oxidative stress conditions |
| title_fullStr |
The autophagic- lysosomal pathway determines the fate of glial cells under manganese- induced oxidative stress conditions |
| title_full_unstemmed |
The autophagic- lysosomal pathway determines the fate of glial cells under manganese- induced oxidative stress conditions |
| title_sort |
autophagic- lysosomal pathway determines the fate of glial cells under manganese- induced oxidative stress conditions |
| publishDate |
2015 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_08915849_v87_n_p237_Gorojod http://hdl.handle.net/20.500.12110/paper_08915849_v87_n_p237_Gorojod |
| _version_ |
1768545288928100352 |