title: Manganese induces mitochondrial dynamics impairment and apoptotic cell death: a study in human Gli36 cells.
abstract: Manganese (Mn) is an essential trace element due to its participation in many physiological processes. However, overexposure to this metal leads to a neurological disorder known as Manganism whose clinical manifestations and molecular mechanisms resemble Parkinson's disease. Several lines of evidence implicate astrocytes as an early target of Mn neurotoxicity being the mitochondria the most affected organelles. The aim of this study was to investigate the possible mitochondrial dynamics alterations in Mn-exposed human astrocytes. Therefore, we employed Gli36 cells which express the astrocytic markers GFAP and S100B. We demonstrated that Mn triggers the mitochondrial apoptotic pathway revealed by increased Bax/Bcl-2 ratio, by the loss of mitochondrial membrane potential and by caspase-9 activation. This apoptotic program may be in turn responsible of caspase-3/7 activation, PARP-1 cleavage, chromatin condensation and fragmentation. In addition, we determined that Mn induces deregulation in mitochondria-shaping proteins (Opa-1, Mfn-2 and Drp-1) expression levels in parallel with the disruption of the mitochondrial network toward to an exacerbated fragmentation. Since mitochondrial dynamics is altered in several neurodegenerative diseases, these proteins could become future targets to be considered in Manganism treatment.
authors.affiliation: Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, IQUIBICEN-CONICET, Buenos Aires, Argentina.
authors.forename: Agustina
authors.initials: A
authors.lastname: Alaimo
authors.forename: Roxana M
authors.initials: RM
authors.lastname: Gorojod
authors.forename: Esteban A
authors.initials: EA
authors.lastname: Miglietta
authors.forename: Alejandro
authors.initials: A
authors.lastname: Villarreal
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Ramos
authors.forename: Mónica L
authors.initials: ML
authors.lastname: Kotler
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects*; D045744:Cell Line, Tumor; D004785:Environmental Pollutants / Q000633:toxicity*; D006801:Humans; D008345:Manganese / Q000633:toxicity*; D053078:Membrane Potential, Mitochondrial; D063154:Mitochondrial Dynamics
chemical_list: D004785:Environmental Pollutants; D008345:Manganese
keywords: Apoptosis; Astrocytes; Human Gli36 cell line; Manganese toxicity; Manganism; Mitochondrial dynamics