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J Cell Sci. 2002 Mar 15;115(Pt 6):1175-88.

Mitochondrial oxidative stress and cell death in astrocytes--requirement for stored Ca2+ and sustained opening of the permeability transition pore.

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Department of Physiology, University College London, London, WC1E 6BT, UK.


The role of oxidative stress is established in a range of pathologies. As mitochondria are a major source of reactive oxygen species (ROS), we have developed a model in which an intramitochondrial photosensitising agent is used to explore the consequences of mitochondrial ROS generation for mitochondrial function and cell fate in primary cells. We have found that, in astrocytes, the interplay between mitochondrial ROS and ER sequestered Ca2+ increased the frequency of transient mitochondrial depolarisations and caused mitochondrial Ca2+ loading from ER stores. The depolarisations were attributable to opening of the mitochondrial permeability transition pore (mPTP). Initially, transient events were seen in individual mitochondria, but ultimately, the mitochondrial potential (Deltapsi(m)) collapsed completely and irreversibly in the whole population. Both ROS and ER Ca2+ were required to initiate these events, but neither alone was sufficient. Remarkably, the transient events alone appeared innocuous, and caused no increase in either apoptotic or necrotic cell death. By contrast, progression to complete collapse of Deltapsi(m) caused necrotic cell death. Thus increased mitochondrial ROS generation initiates a destructive cycle involving Ca2+ release from stores and mitochondrial Ca2+-loading, which further increases ROS production. The amplification of oxidative stress and Ca2+ loading culminates in opening of the mPTP and necrotic cell death in primary brain cells.

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