Ischemic injury to rat forebrain mitochondria and cellular calcium homeostasis

Sciamanna, Michele A.; Zinkel, John L.; Fabi, Alain Y.; Lee, C.P.

doi:10.1016/0167-4889(92)90180-j

Cited by 77 publications

(43 citation statements)

References 52 publications

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“…Inhibition of respiration and/or ADP phosphorylation by elevated Ca 2ϩ is not a unique feature of neuronal mitochondria. A similar injury was observed in earlier studies with mitochondria from tumor (38,52) and transformed neural cells, 2 brain (34,35), and heart (40). The precise mechanisms underlying this injury remain to be elucidated.…”

Section: Discussionsupporting

confidence: 56%

“…Because the extent of Ca 2ϩ -mediated injury may depend on the type of respiratory substrate (31,33,35,36,38,39), we also assessed the effects of glutamate treatment in the presence of the complex II substrate succinate. Mitochondria energized with succinate showed a similar pattern of inhibition of respiration as in the presence of complex I-linked substrates (Fig.…”

Section: Effect Of Glutamate Treatment On Mitochondrial Respiration Amentioning

confidence: 99%

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Excitotoxic Injury to Mitochondria Isolated from Cultured Neurons

Kushnareva¹,

Wiley²,

Ward³

et al. 2005

Journal of Biological Chemistry

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Neuronal death in response to excitotoxic levels of glutamate is dependent upon mitochondrial Ca 2؉ accumulation and is associated with a drop in ATP levels and a loss in ionic homeostasis. Yet the mapping of temporal events in mitochondria subsequent to Ca 2؉ sequestration is incomplete. By isolating mitochondria from primary cultures, we discovered that glutamate treatment of cortical neurons for 10 min caused 44% inhibition of ADP-stimulated respiration, whereas the maximal rate of electron transport (uncoupler-stimulated respiration) was inhibited by ϳ10%.

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Section: Discussionsupporting

confidence: 56%

Section: Effect Of Glutamate Treatment On Mitochondrial Respiration Amentioning

confidence: 99%

Excitotoxic Injury to Mitochondria Isolated from Cultured Neurons

Kushnareva¹,

Wiley²,

Ward³

et al. 2005

Journal of Biological Chemistry

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“…Others have reported state IV respiration being twice as high following a severe TBI in mice (Singh et al, 2006). A short (12-20 min) ischemic= reperfusion event has also been shown to result in an increase in state IV respiration, by *25% (Sciamanna et al, 1992). The lack of any time-dependent changes is indicative of a very rapid injury to the mitochondria within the first hour, which may have important implications in formulating therapeutic interventions.…”

mentioning

confidence: 99%

Early Mitochondrial Dysfunction after Cortical Contusion Injury

Gilmer

Roberts

Joy³

et al. 2009

Journal of Neurotrauma

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Following traumatic brain injury, mitochondria sustain structural and functional impairment, which contributes to secondary damage that can continue for days after the initial injury. The present study investigated mitochondrial bioenergetic changes in the rat neocortex at 1 and 3 h after mild, moderate, and severe injuries. Brains from young adult Sprague-Dawley rats were harvested from the injured and contralateral cortex to assess possible changes in mitochondrial respiration abilities following a unilateral cortical contusion injury. Differential centrifugation was used to isolate synaptic and extrasynaptic mitochondria from cortical tissue. Bioenergetics was assessed using a Clark-type electrode and results were graphed as a function of injury severity and time postinjury. Respiration was significantly affected by all injury severity levels compared to uninjured tissue. Complex 1-and complex 2-driven respirations were affected proportionally to the severity of the injury, indicating that damage to mitochondria may occur on a gradient. Total oxygen utilization, respiratory control ratio, ATP production, and maximal respiration capabilities were all significantly decreased in the injured cortex at both 1 and 3 h post-trauma. Although mitochondria displayed bioenergetic deficits at 1 h following injury, damage was not exacerbated by 3 h. This study stresses the importance of early therapeutic intervention and suggests a window of approximately 1-3 h before greater dysfunction occurs.

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“…Such net accumulation has been documented during ischemia as well as the early reperfusion phase in models of cerebral, cardiac, and neuronal ischemia (21)(22)(23)(24), as well as following excitotoxic challenge to cerebellar granule cells (25). In response to excessive loads, however, mitochondria may incur Ca2+-induced respiratory impairment which compromises the ability of cells to reestablish ionic homeostasis and maintain viable levels of high-energy metabolites such as ATP (23,26). In fact, prevention of mitochondrial Ca2+ sequestration during ischemia using ruthenium red (an inhibitor of the electrophoretic Ca2+ uniporter) can be protective to heart tissue (27) and can prevent glutamate-induced excitotoxicity in cerebellar granule cells (25).…”

mentioning

confidence: 99%

Bcl-2 potentiates the maximal calcium uptake capacity of neural cell mitochondria.

Murphy

Bredesen

Cortopassi

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

397

270

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Expression of the human protooncogene bcl-2 protects neural cells from death induced by many forms of stress, including conditions that greatly elevate intracellular Ca2 . Considering that Bcl-2 is partially localized to mitochondrial membranes and that excessive mitochondrial Ca2+ uptake can impair electron transport and oxidative phosphorylation, the present study tested the hypothesis that mitochondria from Bcl-2-expressing cells have a higher capacity for energy-dependent Ca2+ uptake and a greater resistance to Ca2+-induced respiratory injury than mitochondria from cells that do not express this protein. The overexpression of bcl-2 enhanced the mitochondrial Ca2+ uptake capacity using either digitonin-permeabilized GT1-7 neural cells or isolated GT1-7 mitochondria by 1.7 and 3.9 fold, respectively, when glutamate and malate were used as respiratory substrates. This difference was less apparent when respiration was driven by the oxidation of succinate in the presence of the respiratory complex I inhibitor rotenone. Mitochondria from Bcl-2 expressors were also much more resistant to inhibition of NADH-dependent respiration caused by sequestration of large Ca2+ loads. The enhanced ability of mitochondria within Bcl-2-expressing cells to sequester large quantities of Ca2+ without undergoing profound respiratory impairment provides a plausible mechanism by which Bcl-2 inhibits certain forms of delayed cell death, including neuronal death associated with ischemia and excitotoxicity.

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Ischemic injury to rat forebrain mitochondria and cellular calcium homeostasis

Cited by 77 publications

References 52 publications

Excitotoxic Injury to Mitochondria Isolated from Cultured Neurons

Excitotoxic Injury to Mitochondria Isolated from Cultured Neurons

Early Mitochondrial Dysfunction after Cortical Contusion Injury

Bcl-2 potentiates the maximal calcium uptake capacity of neural cell mitochondria.

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