Mitochondrial calcium and oxidative stress as mediators of ischemic brain injury
Section snippets
Calcium induced mitochondrial dysfunction in acute brain injury
Mitochondrial dysfunction contributes to the etiology of delayed death of neurons, oligodendrocytes, and astrocytes following cerebral ischemia, hypoxia, and trauma [1], [2], [3], [4]. One of the key events that causes mitochondrial injury is an abnormal increase in intracellular Ca2+ [5], [6], [7]. Thus, transient ischemia is accompanied by a gradual rise in [Ca2+]i [8], by calcium sequestration in mitochondria [9], [10], and by mitochondrial bioenergetic dysfunction [11]. Pharmacologic agents
Excitotoxicity, mitochondrial Ca2+, and delayed neuronal Ca2+ deregulation
Excitotoxicity is a process whereby excessive synaptic release of glutamate activates postsynaptic glutamate receptors [40] leading to severe neuronal Ca2+ and Na+ loading [41], culminating in cell death [42]. An important consequence of excitotoxic stimulation is delayed Ca2+ deregulation (DCD), as originally described by Manev et al. [43] and further characterized by the groups of Thayer and coworker [44] and Tymianski et al. [45]. DCD refers to the latent loss of Ca2+ homeostasis of cultured
Influence of Ca2+ on mitochondrial ROS production and the potential relationship to hypoxic brain injury
A compelling body of evidence indicates that oxidative stress caused by reactive oxygen species (ROS) is intimately involved in pathways leading to tissue damage induced by ischemia and reperfusion [49], [78], [79], [80], [81], [82], [83]. ROS are generated in large amounts during reperfusion; [49], [81], [82], [83] mitochondria are thought to produce most of ROS, however, the mechanisms and regulation of mitochondrial ROS are not well understood. Numerous reports imply that massive
Effects of mitochondrial Ca2+ accumulation on ROS production at Complex III of the electron transport chain
The primary ROS produced by mitochondria is superoxide [89]. This highly reactive free radical is extremely short-lived [90], [91], [92], [93], [94] and dismutates either spontaneously or with the help of the mitochondrial superoxide dismutase forming the more ROS, H2O2 [95]. It is not known what mitochondrial redox site or sites are responsible for superoxide production in vivo. Experiments in vitro demonstrate that superoxide can be produced in mitochondria at multiple sites that vary in
Effects of mitochondrial Ca2+ accumulation on ROS production at Complex I of the electron transport chain
One or more sites of superoxide production are located in Complex I of the respiratory chain (reviewed in [97], [98], [99]). The mechanism of ROS generation is not known, primarily because the mechanism of electron transfer in Complex I is not yet clear. The ROS production associated with the physiological electron flow from NADH of the mitochondrial matrix to coenzyme Q in the inner mitochondrial membrane requires the presence of NAD-linked respiratory substrates, e.g., pyruvate, glutamate,
Stimulation of ROS production by Ca2+-activated mitochondrial permeability transition
Activation of the mitochondrial permeability transition pore (PTP) is the most frequently observed consequences of extensive Ca2+ accumulation by mitochondria from various tissues. The PTP is thought to be a large channel in the inner mitochondrial membrane which is normally closed and can be opened by Ca2+ overloading and other factors including oxidative stress. The following are characteristics of the PTP observed in mammalian mitochondria:
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Permeability to solutes with molecular weight <1500
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