Glutamate-induced deregulation of calcium homeostasis and mitochondrial dysfunction in mammalian central neurones

Abstract

Delayed neuronal death following prolonged (10-15 min) stimulation of Glu receptors is known to depend on sustained elevation of cytosolic Ca(2+) concentration ([Ca(2+)](i)) which may persist far beyond the termination of Glu exposure. Mitochondrial depolarization (MD) plays a central role in this Ca(2+) deregulation: it inhibits the uniporter-mediated Ca(2+) uptake and reverses ATP synthetase which enhances greatly ATP consumption during Glu exposure. MD-induced inhibition of Ca(2+) uptake in the face of continued Ca(2+) influx through Glu-activated channels leads to a secondary increase of [Ca(2+)](i) which, in its turn, enhances MD and thus [Ca(2+)](i). Antioxidants fail to suppress this pathological regenerative process which indicates that reactive oxygen species are not involved in its development. In mature nerve cells (>11 DIV), the post-glutamate [Ca(2+)](i) plateau associated with profound MD usually appears after 10-15 min Glu (100 microM) exposure. In contrast, in young cells (<9 DIV) delayed Ca(2+) deregulation (DCD) occurs only after 30-60 min Glu exposure. This difference is apparently determined by a dramatic increase in the susceptibility of mitochondia to Ca(2+) overload during nerve cells maturation. The exact mechanisms of Glu-induced profound MD and its coupling with the impairment of Ca(2+) extrusion following toxic Glu challenge is not clarified yet. Their elucidation demands a study of dynamic changes in local concentrations of ATP, Ca(2+), H(+), Na(+) and protein kinase C using novel methodological approaches.

Mutant Huntingtin Expression Induces Mitochondrial Calcium Handling Defects in Clonal Striatal Cells

“…Mitochondrial dysfunction could result in an increase in the sensitivity of neurons to glutamate, leading to Ca 2ϩ induced cellular dysfunction and eventually cell death (the role of mitochondria in excitotoxicity is discussed in Refs. [43][44][45]. It has been shown previously that decreases in oxidative phosphorylation and state 3 rates are early events in excitotoxicity, and occur prior to the commitment to cell death (46).…”

Cellular and Molecular Mechanisms of Retinal Ganglion Cell Death in Hypoxic-Ischemic Injuries

“…Stimulation of glutamate receptors in chick RGCs in vitro caused calcium influx through NMDA receptorassociated channels and subsequently their death. Increased calcium influx in the neurons causes mitochondrial dysfunction and nNOS generation resulting in neuronal cell death [103,104]. We have shown that expression of nNOS in the RGCs is enhanced in hypoxic injury and that hypoxic induction of nNOS is mediated by nuclear factor kappa B (NF-κB).…”

Pulmonary Hypertension Is a Probable NO/ONOO−Cycle Disease: A Review

“…(11) Other oxidants inactivate the plasma membrane calcium-ATPase, leading to increased levels of intracellular calcium [44][45][46][47][48]; such inactivation of the calcium ATPase has substantial pathophysiological effects [45][46][47][48] and may well contribute to the prolonged impairment of calcium extrusion seen under circumstances, where the NO/ONOO − cycle may have a role [49][50][51].…”

“…(13) While modest elevation of mitochondrial calcium, leads to increased ATP synthesis, substantial elevation of intracellular calcium leads to substantial increases in intramitochondrial calcium, leading to increased superoxide generation in the mitochondrion [49][50][51]53]; large increases in mitochondrial calcium will lead, in some circumstances, to apoptotic cell death [50,51,53]. (14) Intracellular calcium stimulates the nNOS and eNOS forms of nitric oxide synthase, both of which are calcium-dependent enzymes.…”

“…(29) Activation of the NMDA receptors allows calcium in�ux into the cell, raising intracellular calcium levels including mitochondrial calcium levels [1,2,9,49,51,53].…”