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Manganese induces mitochondrial dynamics impairment and apoptotic cell death: a study in human Gli36 cells
Agustina Alaimo1, Roxana M Gorojod, Esteban A Miglietta
1Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, IQUIBICEN-CONICET, Buenos Aires, Argentina.
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.
Insights
Manganese (Mn) overexposure causes neurotoxicity by damaging mitochondria in human astrocytes, leading to apoptosis and fragmented mitochondrial networks. These findings suggest new therapeutic targets for Manganism, a Parkinson
Area of Science:
- Neuroscience
- Cell Biology
- Toxicology
Background:
- Manganese (Mn) is essential but toxic at high levels, causing Manganism, a neurodegenerative disorder mimicking Parkinson's disease.
- Astrocytes are identified as early targets of Mn neurotoxicity, with mitochondria being particularly vulnerable organelles.
Purpose of the Study:
- To investigate alterations in mitochondrial dynamics within human astrocytes exposed to manganese.
- To explore the role of Mn-induced mitochondrial dysfunction in astrocyte apoptosis and neurotoxicity.
Main Methods:
- Utilized Gli36 human astrocyte cell line expressing astrocytic markers GFAP and S100B.
- Assessed mitochondrial apoptotic pathway activation, including Bax/Bcl-2 ratio, mitochondrial membrane potential, and caspase activation.
- Quantified expression levels of mitochondrial dynamics-related proteins (Opa-1, Mfn-2, Drp-1) and analyzed mitochondrial network morphology.
Main Results:
- Manganese exposure triggered the mitochondrial apoptotic pathway, evidenced by increased Bax/Bcl-2 ratio, loss of mitochondrial membrane potential, and caspase-9 activation.
- Downstream caspase-3/7 activation, PARP-1 cleavage, and DNA fragmentation confirmed the apoptotic cascade.
- Manganese induced significant deregulation in Opa-1, Mfn-2, and Drp-1 expression, leading to an increasingly fragmented mitochondrial network.
Conclusions:
- Manganese neurotoxicity in astrocytes involves the activation of the mitochondrial apoptotic pathway and significant disruption of mitochondrial dynamics.
- Alterations in mitochondrial network fragmentation and the expression of mitochondria-shaping proteins are key features of Mn-induced astrocyte damage.
- Mitochondria-shaping proteins represent potential therapeutic targets for mitigating Manganism and related neurodegenerative conditions.
