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Abstract:

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.

Registro:

Documento: Artículo
Título:The autophagic- lysosomal pathway determines the fate of glial cells under manganese- induced oxidative stress conditions
Autor:Gorojod, R.M.; Alaimo, A.; Porte Alcon, S.; Pomilio, C.; Saravia, F.; Kotler, M.L.
Filiación:Departamento de Química Biológica, Universidad de Buenos Aires, Instituto de Química Biológica, Ciencias Exactas y Naturales (IQUIBICEN), Avda. Intendente Güiraldes 2 160Buenos Aires C1428EGA, Argentina
Departamento de Química Biológica, Universidad de Buenos Aires, Instituto de Biología y Medicina Experimental (IBYME)Buenos Aires, Argentina
Palabras clave: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
Año:2015
Volumen:87
Página de inicio:237
Página de fin:251
DOI: http://dx.doi.org/10.1016/j.freeradbiomed.2015.06.034
Título revista:Free Radical Biology and Medicine
Título revista abreviado:Free Radic. Biol. Med.
ISSN:08915849
CODEN:FRBME
CAS:bafilomycin A1, 88899-55-2; cathepsin B, 9047-22-7; dansylcadaverine, 10121-91-2; manganese, 16397-91-4, 7439-96-5; protein bcl 2, 219306-68-0; LC3 protein, rat; Manganese; Microtubule-Associated Proteins; Reactive Oxygen Species
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_08915849_v87_n_p237_Gorojod

Referencias:

  • Roth, J.A., Are there common biochemical and molecular mechanisms controlling manganism and parkisonism (2009) Neuromolecular Med., 11, pp. 281-296
  • Couper, J., On the effects of black oxide of manganese when inhaled into the lungs (1837) Br. Ann. Med. Pharmacol., 1, pp. 41-42
  • Normandin, L., Hazell, A.S., Manganese neurotoxicity: An update of pathophysiologic mechanisms (2002) Metab. Brain Dis., 17, pp. 375-387
  • Guilarte, T.R., Manganese and Parkinson's disease: A critical review and new findings (2010) Environ. Health Perspect., 118, pp. 1071-1080
  • Erikson, K.M., Dobson, A.W., Dorman, D.C., Aschner, M., Manganese exposure and induced oxidative stress in the rat brain (2004) Sci. Total Environ., 334-335, pp. 409-416
  • Fernsebner, K., Zorn, J., Kanawati, B., Walker, A., Michalke, B., Manganese leads to an increase in markers of oxidative stress as well as to a shift in the ratio of Fe(II)/(III) in rat brain tissue (2014) Met. Integr. Biometal Sci., 6, pp. 921-931
  • Xu, B., Xu, Z.-F., Deng, Y., Effect of manganese exposure on intracellular Ca2+ homeostasis and expression of NMDA receptor subunits in primary cultured neurons (2009) Neurotoxicology, 30, pp. 941-949
  • Filomeni, G., De Zio, D., Cecconi, F., Oxidative stress and autophagy: The clash between damage and metabolic needs (2015) Cell Death Differ., 22, pp. 377-388
  • Zhang, J., Autophagy and mitophagy in cellular damage control (2013) Redox Biol., 1, pp. 19-23
  • Mariño, G., Niso-Santano, M., Baehrecke, E.H., Kroemer, G., Self-consumption: The interplay of autophagy and apoptosis (2014) Nat. Rev. Mol. Cell Biol., 15, pp. 81-94
  • Klionsky, D.J., Abdalla, F.C., Abeliovich, H., Abraham, R.T., Acevedo-Arozena, A., Adeli, K., Agholme, L., Anantharam, V., Guidelines for the use and interpretation of assays for monitoring autophagy (2012) Autophagy, 8, pp. 445-544
  • Boya, P., Kroemer, G., Lysosomal membrane permeabilization in cell death (2008) Oncogene, 27, pp. 6434-6451
  • Rao, K.V.R., Norenberg, M.D., Manganese induces the mitochondrial permeability transition in cultured astrocytes (2004) J. Biol. Chem., 279, pp. 32333-32338
  • Zwingmann, C., Leibfritz, D., Hazell, A.S., Energy metabolism in astrocytes and neurons treated with manganese: Relation among cell-specific energy failure, glucose metabolism, and intercellular trafficking using multinuclear NMR-spectroscopic analysis (2003) J. Cereb. Blood Flow Metab., 23, pp. 756-771
  • Gonzalez, L.E., Juknat, A.A., Venosa, A.J., Verrengia, N., Kotler, M.L., Manganese activates the mitochondrial apoptotic pathway in rat astrocytes by modulating the expression of proteins of the Bcl-2 family (2008) Neurochem. Int., 53, pp. 408-415
  • Alaimo, A., Gorojod, R.M., Beauquis, J., Muñoz, M.J., Saravia, F., Kotler, M.L., Deregulation of Mitochondria-Shaping Proteins Opa-1 and Drp-1 in Manganese-Induced Apoptosis (2014) PLoS ONE, 9
  • Alaimo, A., Gorojod, R.M., Kotler, M.L., The extrinsic and intrinsic apoptotic pathways are involved in manganese toxicity in rat astrocytoma C6 cells (2011) Neurochem. Int., 59, pp. 297-308
  • Alaimo, A., Gorojod, R.M., Miglietta, E.A., Villarreal, A., Ramos, A.J., Kotler, M.L., Manganese induces mitochondrial dynamics impairment and apoptotic cell death: A study in human Gli36 cells (2013) Neurosci. Lett.
  • Benda, P., Lightbody, J., Sato, G., Levine, L., Sweet, W., Differentiated rat glial cell strain in tissue culture (1968) Science, 161, pp. 370-371
  • Mosmann, T., Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays (1983) J. Immunol. Methods, 65, pp. 55-63
  • Repetto, G., Del Peso, A., Zurita, J.L., Neutral red uptake assay for the estimation of cell viability/cytotoxicity (2008) Nat. Protoc., 3, pp. 1125-1131
  • Jiang, H., White, E.J., Conrad, C., Gomez-Manzano, C., Fueyo, J., Autophagy pathways in glioblastoma (2009) Methods Enzymol., 453, pp. 273-286
  • Biederbick, A., Kern, H.F., Elsässer, H.P., Monodansylcadaverine (MDC) is a specific in vivo marker for autophagic vacuoles (1995) Eur. J. Cell Biol., 66, pp. 3-14
  • Paxinos, G., Watson, C., (1998) The Rat Brain in Stereotaxic Coordinates, , 2nd ed Academic Press San Diego
  • Borenfreund, E., Puerner, J.A., Toxicity determined in vitro by morphological alterations and neutral red absorption (1985) Toxicol. Lett., 24, pp. 119-124
  • Pivtoraiko, V.N., Stone, S.L., Roth, K.A., Shacka, J.J., Oxidative stress and autophagy in the regulation of lysosome-dependent neuron death (2009) Antioxid. Redox Signal., 11, pp. 481-496
  • Munafó, D.B., Colombo, M.I., A novel assay to study autophagy: Regulation of autophagosome vacuole size by amino acid deprivation (2001) J. Cell Sci., 114, pp. 3619-3629
  • Kabeya, Y., Mizushima, N., Ueno, T., Yamamoto, A., Kirisako, T., Noda, T., Kominami, E., Yoshimori, T., LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing (2000) EMBO J., 19, pp. 5720-5728
  • Kang, R., Zeh, H.J., Lotze, M.T., Tang, D., The Beclin 1 network regulates autophagy and apoptosis (2011) Cell Death Differ., 18, pp. 571-580
  • Pattingre, S., Tassa, A., Qu, X., Garuti, R., Liang, X.H., Mizushima, N., Packer, M., Levine, B., Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy (2005) Cell, 122, pp. 927-939
  • Levine, B., Sinha, S., Kroemer, G., Bcl-2 family members: Dual regulators of apoptosis and autophagy (2008) Autophagy, 4, pp. 600-606
  • Geng, J., Klionsky, D.J., The Atg8 and Atg12 ubiquitin-like conjugation systems in macroautophagy. 'Protein modifications: Beyond the usual suspects' review series (2008) EMBO Rep., 9, pp. 859-864
  • Mizushima, N., Yamamoto, A., Hatano, M., Kobayashi, Y., Kabeya, Y., Suzuki, K., Tokuhisa, T., Yoshimori, T., Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells (2001) J. Cell Biol., 152. , 657-68
  • MacVicar, Mitophagy, T., (2013) Essays Biochem., 55, pp. 93-104
  • Twig, G., Shirihai, O.S., The Interplay between Mitochondrial Dynamics and Mitophagy (2011) Antioxid. Redox Signal., 14, pp. 1939-1951
  • Wang, J., Whiteman, M.W., Lian, H., Wang, G., Singh, A., Huang, D., Denmark, T., A non-canonical MEK/ERK signaling pathway regulates autophagy via regulating Beclin 1 (2009) J. Biol. Chem., 284, pp. 21412-21424
  • Wei, Y., Pattingre, S., Sinha, S., Bassik, M., Levine, B., JNK1-Mediated Phosphorylation of Bcl-2 Regulates Starvation-Induced Autophagy (2008) Mol. Cell, 30, pp. 678-688
  • Webber, J.L., Regulation of autophagy by p38α MAPK (2010) Autophagy, 6, pp. 292-293
  • Kondo, Y., Kanzawa, T., Sawaya, R., Kondo, S., The role of autophagy in cancer development and response to therapy (2005) Nat. Rev. Cancer, 5, pp. 726-734
  • Kroemer, G., Mariño, G., Levine, B., Autophagy and the integrated stress response (2010) Mol. Cell, 40, pp. 280-293
  • Repetto, G., Sanz, P., Neutral red uptake, cellular growth and lysosomal function: In vitro effects of 24 metals (1993) ATLA, 21, pp. 501-507
  • Nixon, R.A., Yang, D.S., Lee, J.H., Neurodegenerative lysosomal disorders: A continuum from development to late age (2008) Autophagy, 4, pp. 590-599
  • Heng, M.Y., Detloff, P.J., Paulson, H.L., Albin, R.L., Early alterations of autophagy in Huntington disease-like mice (2010) Autophagy, 6, pp. 1206-1208
  • Lee, J.A., Beigneux, A., Ahmad, S.T., Young, S.G., Gao, F.-B., ESCRT-III Dysfunction Causes Autophagosome Accumulation and Neurodegeneration (2007) Curr. Biol., 17, pp. 1561-1567
  • Greiner-Tollersrud, O.K., Berg, T., (2006) Lysosomal Storage Disorders, pp. 60-73. , P. Saftig, Springer-Verlag New York Inc
  • Nixon, R.A., The role of autophagy in neurodegenerative disease (2013) Nat. Med., 19, pp. 983-997
  • Takahashi, T., Kitaoka, K.I., Ogawa, Y., Kobayashi, T., Seguchi, H., Tani, T., Yoshida, S., Lysosomal dysfunction on hydrogen peroxide-induced apoptosis of osteoarthritic chondrocytes (2004) Int. J. Mol. Med., 14, pp. 197-200
  • Zhang, J., Cao, R., Cai, T., Aschner, M., Zhao, F., Yao, T., Chen, Y., Chen, J., The role of autophagy dysregulation in manganese-induced dopaminergic neurodegeneration (2013) Neurotox. Res., 24, pp. 478-490
  • Sridharan, S., Jain, K., Basu, A., Regulation of Autophagy by Kinases (2011) Cancers, 3, pp. 2630-2654
  • Yin, Z., Aschner, J.L., Dos Santos, A.P., Aschner, M., Mitochondrial-dependent manganese neurotoxicity in rat primary astrocyte cultures (2008) Brain Res., 1203, pp. 1-11
  • Rao, K.V.R., Jayakumar, A.R., Reddy, P.V.B., Tong, X., Curtis, K.M., Norenberg, M.D., Aquaporin-4 in manganese-treated cultured astrocytes (2010) Glia, 58, pp. 1490-1499
  • Exil, V., Ping, L., Yu, Y., Chakraborty, S., Caito, S.W., Wells, K.S., Karki, P., Aschner, M., Activation of MAPK and FoxO by Manganese (Mn) in Rat Neonatal Primary Astrocyte Cultures (2014) PLoS ONE, 9
  • Peres, T.V., Pedro, D.Z., De Cordova, F.M., Lopes, M.W., Gonçalves, F.M., Nedel Mendes-De-Aguiar, C.B., Walz, R., Leal, R.B., In Vitro Manganese Exposure Disrupts MAPK Signaling Pathways in Striatal and Hippocampal Slices from Immature Rats (2013) BioMed Res. Int., , 2013
  • Zhang, Y., Wu, Y., Cheng, Y., Zhao, Z., Tashiro, S., Onodera, S., Ikejima, T., Fas-mediated autophagy requires JNK activation in HeLa cells (2008) Biochem. Biophys. Res. Commun., 377, pp. 1205-1210
  • Alaimo, A., (2012) Manganese-induced Neurotoxicity. Apoptotic Death Pathways and Mitochondrial Dynamics Role, , Universidad de Buenos Aires Argentina PhD dissertation
  • Zhang, S., Zhou, Z., Fu, J., Effect of manganese chloride exposure on liver and brain mitochondria function in rats (2003) Environ. Res., 93, pp. 149-157
  • Gavin, C.E., Gunter, K.K., Gunter, T.E., Manganese and calcium efflux kinetics in brain mitochondria. Relevance to manganese toxicity (1990) Biochem. J., 266, pp. 329-334
  • Suzuki, H., Wada, O., Inoue, K., Tosaka, H., Ono, T., Role of brain lysosomes in the development of manganese toxicity in mice (1983) Toxicol. Appl. Pharmacol., 71, pp. 422-429
  • Ono, K., Kim, S.O., Han, J., Susceptibility of Lysosomes to Rupture Is a Determinant for Plasma Membrane Disruption in Tumor Necrosis Factor Alpha-Induced Cell Death (2003) Mol. Cell. Biol., 23, pp. 665-676
  • Nishihara, T., Akifusa, S., Koseki, T., Kato, S., Muro, M., Hanada, N., Specific inhibitors of vacuolar type H(+)-ATPases induce apoptotic cell death (1995) Biochem. Biophys. Res. Commun., 212, pp. 255-262
  • Pivtoraiko, V.N., Harrington, A.J., Mader, B.J., Luker, A.M., Caldwell, G.A., Caldwell, K.A., Roth, K.A., Shacka, J.J., Low-dose bafilomycin attenuates neuronal cell death associated with autophagy-lysosome pathway dysfunction (2010) J. Neurochem., 114, pp. 1193-1204
  • Shacka, J.J., Klocke, B.J., Shibata, M., Uchiyama, Y., Datta, G., Schmidt, R.E., Roth, K.A., Bafilomycin A1 inhibits chloroquine-induced death of cerebellar granule neurons (2006) Mol. Pharmacol., 69, pp. 1125-1136

Citas:

---------- APA ----------
Gorojod, R.M., Alaimo, A., Porte Alcon, S., Pomilio, C., Saravia, F. & Kotler, M.L. (2015) . The autophagic- lysosomal pathway determines the fate of glial cells under manganese- induced oxidative stress conditions. Free Radical Biology and Medicine, 87, 237-251.
http://dx.doi.org/10.1016/j.freeradbiomed.2015.06.034
---------- CHICAGO ----------
Gorojod, R.M., Alaimo, A., Porte Alcon, S., Pomilio, C., Saravia, F., Kotler, M.L. "The autophagic- lysosomal pathway determines the fate of glial cells under manganese- induced oxidative stress conditions" . Free Radical Biology and Medicine 87 (2015) : 237-251.
http://dx.doi.org/10.1016/j.freeradbiomed.2015.06.034
---------- MLA ----------
Gorojod, R.M., Alaimo, A., Porte Alcon, S., Pomilio, C., Saravia, F., Kotler, M.L. "The autophagic- lysosomal pathway determines the fate of glial cells under manganese- induced oxidative stress conditions" . Free Radical Biology and Medicine, vol. 87, 2015, pp. 237-251.
http://dx.doi.org/10.1016/j.freeradbiomed.2015.06.034
---------- VANCOUVER ----------
Gorojod, R.M., Alaimo, A., Porte Alcon, S., Pomilio, C., Saravia, F., Kotler, M.L. The autophagic- lysosomal pathway determines the fate of glial cells under manganese- induced oxidative stress conditions. Free Radic. Biol. Med. 2015;87:237-251.
http://dx.doi.org/10.1016/j.freeradbiomed.2015.06.034