Influence of calcium and iron on cell death and mitochondrial function in oxidatively stressed astrocytes

Astrocytes protect neurons and oligodendrocytes by buffering ions, neurotra nsmitters, and providing metabolic support, However, astrocytes are also vu lnerable to oxidative stress, which may affect their protective and support ive functions, This paper examines the influence of calcium and iron on ast rocytes and determines if cell death could be mediated by mitochondrial dys function, We provide evidence that the events associated with peroxide-indu ced death of astrocytes involves generation of superoxide at the site of mi tochondria, loss of mitochondrial membrane potential, and depletion of ATP, These events are iron-mediated, with iron loading exacerbating and iron ch elation reducing oxidative stress. Iron chelation maintained the mitochondr ial membrane potential, prevented peroxide-induced elevations in superoxide levels, and preserved ATP levels, Although increased intracellular calcium occurred after oxidative stress to astrocytes, the calcium increase was no t necessary for collapse of mitochondrial membrane potential, Indeed, when astrocytes were oxidatively stressed In the absence of extracellular calciu m, cell death was enhanced, mitochondrial membrane potential collapsed at a n earlier time point, and superoxide levels increased, Additionally, our da ta do not support opening of the mitochondrial permeability transition pore as part of the mechanism of peroxide-induced oxidative stress of astrocyte s, We conclude that the increase in intracellular calcium following peroxid e exposure does not mediate astrocytic death and may even provide a protect ive function, Finally, the vulnerability of astrocytes and their mitochondr ia to oxidative stress correlates more closely with iron availability than with increased intracellular calcium. (C) 1999 Wiley-Liss, Inc.