Manganese activates the mitochondrial apoptotic pathway in rat astrocytes by modulating the expression of proteins of the Bcl-2 family |
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| Institution: | 1. Division of Clinical Pharmacology and Pediatric Toxicology, Vanderbilt University Medical Center, Nashville, TN, USA;2. The Kennedy Center for Research on Human Development, Vanderbilt University Medical Center, Nashville, TN, USA;3. Center in Molecular Toxicology, Vanderbilt University Medical Center, Nashville, TN, USA;4. Center for Molecular Neuroscience, Vanderbilt University Medical Center, Nashville, TN, USA |
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| Abstract: | Manganese induces the central nervous system injury leading to manganism, by mechanisms not completely understood. Chronic exposure to manganese generates oxidative stress and induces the mitochondrial permeability transition. In the present study, we characterized apoptotic cell death mechanisms associated with manganese toxicity in rat cortical astrocytes and demonstrated that (i) Mn treatment targets the mitochondria and induces mitochondrial membrane depolarization followed by cytochrome c release to the cytoplasm, (ii) Mn induces both effector caspases 3/7 and 6 as well as PARP-1 cleavage and (iii) Mn shifts the balance of cell death/survival of Bcl-2 family proteins to favor the apoptotic demise of astrocytes. Our model system using cortical rat astrocytes treated with Mn would emerge as a good tool for investigations aimed to elucidate the role of apoptosis in manganism. |
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