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

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

^* Author for correspondence (e-mail:m.duchen{at}ucl.ac.uk )

Accepted 19 December 2001

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 (_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 _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.

Key words: Mitochondria, Oxidative stress, Permeability transition pore, Photosensitization, Intracellular calcium

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