Growth Factors Prevent Mitochondrial Dysfunction, Loss of Calcium Homeostasis, and Cell Injury, but Not ATP Depletion in Hippocampal Neurons Deprived of Glucose

Mattson, Mark P.; Zhang, Ying; Bose, Soma C.

doi:10.1006/exnr.1993.1066

Cited by 261 publications

(137 citation statements)

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“…We c~ ,nclude that the GLU-induced mitochondrial membrane potential collapse in granule cells was induced by the rise in intracellular Ca ~+. Similar results, albeit after long-term (up t¢ 3 h) GLU exposure of cultivated hippocampal neurons, h~tve been obtained by Mattson et al [9]. However, Dugan el al.…”

Section: Resultssupporting

confidence: 77%

“…It has been found that processes inducing neuronal degeneration after the hyperstimulation of glutamate receptors result in Ca 2+ and Na + influx into the cell through ion channels activated by GLU [4,5]. This, in turn, results in overloading of neuronal cvtosol with these cations [6,7] and in subsequent distortion of the cellular energetics [8,9] and activation of Ca2+-dependent proteolytic and lipolytic enzymes. Many drugs causing cellular d~tmage are known to use rnitochondria as a primary target [10,11].…”

Section: Introductionmentioning

confidence: 99%

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Neurotoxic glutamate treatment of cultured cerebellar granule cells induces Ca²⁺‐dependent collapse of mitochondrial membrane potential and ultrastructural alterations of mitochondria

et al. 1996

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Rhodamine 123 staining and electron microscopy were used to reveal a correlation between the ultrastructural and functional state of cultured cerebellar granule cells after short glutamate treatment. Glutamate exposure (15 min, 100 lxM) in Mg2+-free solution caused considerable ultrastructural alterations in a granule cell: clumping of the chromatin, swelling of the endoplasmic reticulum and mitochondria, and disruption of the mitochondrial cristae. After glutamate treatment, the mitochondria of the neurons lost their ability to sequester rhodamine 123. Both the N-methyl-D-nspartate receptor channel blocker MK-801 (30 ItM) and cobalt chloride (2 mM) prevented the deteriorative effects of glutamate. These data suggest that glutaumte-induced Ca 2+ overload of the neurons can lead to nonspecific permeability of the inner mitochondrial membrane, resulting in neuronal death.

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Section: Resultssupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Neurotoxic glutamate treatment of cultured cerebellar granule cells induces Ca²⁺‐dependent collapse of mitochondrial membrane potential and ultrastructural alterations of mitochondria

et al. 1996

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“…Second, calcium and sodium influx may stimulate the consumption of ATP through Ca 2ϩ -ATPase and Na ϩ /K ϩ -ATPase. Moreover, calcium overload will ultimately disrupt mitochondrial function (Mattson et al, 1993;Medrano and Fox, 1994;Minezaki et al, 1994;Schinder et al, 1996;White and Reynolds, 1996). Cycloheximide has no effect on 3-NP-induced decline in cellular ATP levels, suggesting that loss of ATP is indeed an initial event and that cycloheximide acts downstream to ATP loss.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Cell Death Induced by the Mitochondrial Toxin 3-Nitropropionic Acid: Acute Excitotoxic Necrosis and Delayed Apoptosis

1997

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Impaired energy metabolism may play an important role in neuronal cell death after brain ischemia and in late-onset neurodegenerative diseases. Both excitotoxic necrosis and apoptosis have been implicated in cell death induced by metabolic impairment. However, the factors that determine whether cells undergo apoptosis or necrosis are not known. In the present study, metabolic impairment was induced by 3-nitropropionic acid (3-NP), a suicide inhibitor of succinate dehydrogenase. Treatment of cultured rat hippocampal neurons with 3-NP resulted in two types of cell death with distinct morphological, pharmacological, and biochemical features. A rapid necrotic cell death, characterized by cell swelling and nuclear shrinkage, could be completely prevented by the NMDA receptor antagonist MK-801 (10 M) and dose-dependently potentiated by low micromolar levels of extracellular glutamate. A slowly evolving apoptotic death, characterized by nuclear fragmentation, was not attenuated by MK-801 but was prevented by cycloheximide (1 g/ml). The combination of MK-801 and cycloheximide resulted in an almost complete protection against 3-NP-induced cell death. DNA fragmentation, detected by the terminal deoxynucleotidyl transferase-mediated dUTP-X 3Ј nick end-labeling technique, was a late event in apoptosis and also occurred after necrotic cell death. ATP depletion was an early event in the 3-NP-induced neuronal degeneration, and the decline in ATP was exacerbated by glutamate. We conclude that 3-NP triggers two separate cell death pathways: an excitotoxic necrosis as a result of NMDA receptor activation and a delayed apoptosis that is NMDA receptor-independent. Mildly elevated levels of extracellular glutamate shift the cell death mechanism from apoptosis to necrosis.Key words: energy metabolism; succinate dehydrogenase; 3-nitropropionic acid; excitotoxicity; apoptosis; necrosis; nuclear fragmentation; TUNEL; ATP Neuronal function and survival depend on a continuous supply of glucose and oxygen, used to generate ATP through glycolysis and mitochondrial respiration. A perturbation in energy metabolism during conditions such as ischemia, stroke, and brain trauma may cause irreversible neuronal injury. An age-related decline in energy metabolism also may contribute to neuronal loss during normal aging, as well as in neurodegenerative diseases (Wallace, 1994;Beal, 1995).There are discrepancies in the findings regarding the mechanisms of neuronal cell death after metabolic impairment. A large body of evidence supports the "secondary excitotoxicity" hypothesis that a loss of ATP leads to membrane depolarization, removal of the voltage-dependent Mg 2ϩ block of the NMDA receptor, and subsequent activation of NMDA receptor (for review, see Beal, 1992). Both in vivo and in vitro studies have shown that metabolic inhibitors potentiate glutamate and NMDA toxicity (Weller and

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“…SH-SY5Y cells possess functional trkA receptors; NGF can differentiate SH-SY5Y cells (Baker et al, 1989;Poluha et al, 1995). NGF may stabilize calcium homeostasis by altering calcium binding proteins, modifying receptor function, restoring mitochondrial transmembrane potential, inducing Bcl-2, and preventing release of cytochrome c from mitochondria, or a host of other mechanisms (Thoenen and Barde, 1980;Mattson et al, 1993c;Kluck et al, 1997;Yang et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Calcium Homeostasis and Reactive Oxygen Species Production in Cells Transformed by Mitochondria from Individuals with Sporadic Alzheimer’s Disease

Sheehan

Swerdlow

Miller³

et al. 1997

J. Neurosci.

238

140

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Alzheimer's disease (AD) is associated with defects in mitochondrial function. Mitochondrial-based disturbances in calcium homeostasis, reactive oxygen species (ROS) generation, and amyloid metabolism have been implicated in the pathophysiology of sporadic AD. The cellular consequences of mitochondrial dysfunction, however, are not known. To examine these consequences, mitochondrially transformed cells (cybrids) were created from AD patients or disease-free controls. Mitochondria from platelets were fused to 0 cells created by depleting the human neuroblastoma line SH-SY5Y of its mitochondrial DNA (mtDNA). AD cybrids demonstrated a 52% decrease in electron transport chain (ETC) complex IV activity but no difference in complex I activity compared with control cybrids or SH-SY5Y cells. This mitochondrial dysfunction suggests a transferable mtDNA defect associated with AD. ROS generation was elevated in the AD cybrids. AD cybrids also displayed an increased basal cytosolic calcium concentration and enhanced sensitivity to inositol-1,4,5-triphosphate (InsP 3 )-mediated release. Furthermore, they recovered more slowly from an elevation in cytosolic calcium induced by the InsP 3 agonist carbachol. Mitochondrial calcium buffering plays a major role after this type of perturbation. ␤-amyloid (25-35) peptide delayed the initiation of calcium recovery to a carbachol challenge and slowed the recovery rate. Nerve growth factor reduced the carbachol-induced maximum and moderated the recovery kinetics. Succinate increased ETC activity and partially restored the AD cybrid recovery rate. These subtle alterations in calcium homeostasis and ROS generation might lead to increased susceptibility to cell death under circumstances not ordinarily toxic.

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Growth Factors Prevent Mitochondrial Dysfunction, Loss of Calcium Homeostasis, and Cell Injury, but Not ATP Depletion in Hippocampal Neurons Deprived of Glucose

Cited by 261 publications

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Neurotoxic glutamate treatment of cultured cerebellar granule cells induces Ca²⁺‐dependent collapse of mitochondrial membrane potential and ultrastructural alterations of mitochondria

Neurotoxic glutamate treatment of cultured cerebellar granule cells induces Ca²⁺‐dependent collapse of mitochondrial membrane potential and ultrastructural alterations of mitochondria

Mechanisms of Cell Death Induced by the Mitochondrial Toxin 3-Nitropropionic Acid: Acute Excitotoxic Necrosis and Delayed Apoptosis

Calcium Homeostasis and Reactive Oxygen Species Production in Cells Transformed by Mitochondria from Individuals with Sporadic Alzheimer’s Disease

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Growth Factors Prevent Mitochondrial Dysfunction, Loss of Calcium Homeostasis, and Cell Injury, but Not ATP Depletion in Hippocampal Neurons Deprived of Glucose

Cited by 261 publications

References 0 publications

Neurotoxic glutamate treatment of cultured cerebellar granule cells induces Ca2+‐dependent collapse of mitochondrial membrane potential and ultrastructural alterations of mitochondria

Neurotoxic glutamate treatment of cultured cerebellar granule cells induces Ca2+‐dependent collapse of mitochondrial membrane potential and ultrastructural alterations of mitochondria

Mechanisms of Cell Death Induced by the Mitochondrial Toxin 3-Nitropropionic Acid: Acute Excitotoxic Necrosis and Delayed Apoptosis

Calcium Homeostasis and Reactive Oxygen Species Production in Cells Transformed by Mitochondria from Individuals with Sporadic Alzheimer’s Disease

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Neurotoxic glutamate treatment of cultured cerebellar granule cells induces Ca²⁺‐dependent collapse of mitochondrial membrane potential and ultrastructural alterations of mitochondria

Neurotoxic glutamate treatment of cultured cerebellar granule cells induces Ca²⁺‐dependent collapse of mitochondrial membrane potential and ultrastructural alterations of mitochondria