Calcium‐induced Cytochrome <i>c</i> release from CNS mitochondria is associated with the permeability transition and rupture of the outer membrane

Brustovetsky, Nickolay; Brustovetsky, Tatiana; Jemmerson, Ronald; Dubinsky, Janet M.

doi:10.1046/j.0022-3042.2001.00671.x

Cited by 229 publications

(232 citation statements)

References 48 publications

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“…The release of cytochrome c from the intermembranous space appeared to be dependent of the rupture of the outer mitochondrial membrane (Brustovetsky et al, 2002). A second occurrence of ruptured outer mitochondrial membrane in mitochondrial fractions induced to undergo permeability transition may be observed with a magnifying lens in the right superior quadrant of Figure 4B from Petronilli et al (1993) directly on the journal page.…”

Section: Discussionmentioning

confidence: 88%

Morphology of mitochondrial permeability transition: Morphometric volumetry in apoptotic cells

et al. 2004

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Here we report on the mitochondrial permeability transition (MPT), which refers to the morphology of mitochondria whose inner membrane has lost its selective permeability. In all types of apoptotic cells so far examined, we found outer mitochondrial membranes that had been ruptured. These mitochondria present a swollen matrix covered by an inner membrane herniating into the cytoplasm through the breached outer membrane. Similarly ruptured outer mitochondrial membranes have been reported in studies on mitochondrial fractions induced to undergo MPT, carried out by others. Our observations were made on five types of rat tissue cells and six different cultured cell lines in the early stages of apoptosis. Samples from the cell lines HL-60, HeLa, WEHI-164, and a special batch of PC-12 cells were subjected to various apoptogenic agents and analyzed morphometrically. Nonapoptotic companion cells with unaltered nuclear structure (CUNS) were also analyzed. The mitochondrial volume in m 3 and the volume fraction of the cytoplasm occupied by mitochondria in cells with typical nuclear signs of apoptosis and also in CUNS were evaluated. The volume of the mitochondria with ruptured membrane represents at least 69% (47-89%) of the total mitochondrial volume of the apoptotic cells. Thus, a considerable fraction of the cellular mitochondrial mass is or was in the state of permeability transition and probably involved in enhancement of the apoptotic program. In all samples, a fraction of the cells with normal nuclei possessed mitochondria with breached outer membranes as described above. In these cells, MPT occurred before the appearance of the typical nuclear phenotype of the apoptotic cells.

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Section: Discussionmentioning

confidence: 88%

Morphology of mitochondrial permeability transition: Morphometric volumetry in apoptotic cells

et al. 2004

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“…An increased level of O 2 ·) following DCD could reflect either increased formation or decreased trapping, for example as a consequence of a failure of the depolarized mitochondria to maintain glutathione reduction. NMDA can cause release of cytochrome c from mitochondria in cultured hippocampal (Lankiewicz et al 2000) or cortical Brustovetsky et al 2002) neurons. While intact depolarized mitochondria do not produce superoxide (Korshunov et al 1997), mitochondria that have released cytochrome c, and hence the ability to transfer electrons out of complex III, do generate the radical (Cai and Jones 1998).…”

Section: Discussionmentioning

confidence: 99%

Relationships between superoxide levels and delayed calcium deregulation in cultured cerebellar granule cells exposed continuously to glutamate

Vesce

Kirk

Nicholls

2004

Journal of Neurochemistry

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The relationship is investigated between superoxide levels in single cultured rat cerebellar granule neurons exposed continuously to glutamate in low KCl medium and the deregulation of cytoplasmic Ca 2+ . Cells that maintain a regulated cytoplasmic-free Ca 2+ and mitochondrial polarization in the presence of glutamate show no increase in superoxide levels until the onset of cytoplasmic Ca 2+ deregulation. Oxidative stress of mitochondrial origin is readily detectable, as the inhibitors rotenone and antimycin A markedly increase superoxide levels with no effect on cytoplasmic-free Ca 2+ . The potent cell-permeant superoxide dismutase/catalase mimetic manganese tetrakis (N-ethylpyridinium-2yl) porphyrin, MnTE-PyP, abolishes the deregulation-related increase in superoxide but has no effect on deregulation itself. A combination of catalase with the free radical scavenger 4-hydroxy-TEMPO also fails to reduce deregulation. Following the loss of Ca 2+ homeostasis nuclei undergo condensation; this morphological change is not inhibited by MnTE-PyP and cannot account for the increased ethidium fluorescence. Phospholipase A 2 inhibitors decrease the deregulation-related increase in superoxide without protecting against deregulation. In conclusion, our study indicates that deregulation is not caused by NMDA receptor-mediated oxidative stress as NMDA receptor activation does not increase superoxide levels until the onset of deregulation. Furthermore, the majority of superoxide is produced in the cytoplasm rather than in mitochondria.

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“…This increases intracellular Ca 2 + (Satrustegui and Richter, 1984), which induces permeability transition pores in neuronal mitochondria (Crompton, 1999). Cytochrome c, which transports electrons from complex III to IV, is consequently translocated from the inner mitochondrial membrane to the cytoplasm (Brustovetsky et al, 2002). This translocation is considered a key step in the initiation of mitochondria-dependent apoptosis, since cytochrome c, once present in the cytoplasm, comprises an upstream signal in the apoptotic cascade (Polster and Fiskum, 2004).…”

Section: Apoptosismentioning

confidence: 99%

Neuro-oxidative-nitrosative stress in sepsis

Berg

Møller

Bailey

2011

J Cereb Blood Flow Metab

140

109

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Neuro-oxidative-nitrosative stress may prove the molecular basis underlying brain dysfunction in sepsis. In the current review, we describe how sepsis-induced reactive oxygen and nitrogen species (ROS/RNS) trigger lipid peroxidation chain reactions throughout the cerebrovasculature and surrounding brain parenchyma, due to failure of the local antioxidant systems. ROS/RNS cause structural membrane damage, induce inflammation, and scavenge nitric oxide (NO) to yield peroxynitrite (ONOO À ). This activates the inducible NO synthase, which further compounds ONOO À formation. ROS/RNS cause mitochondrial dysfunction by inhibiting the mitochondrial electron transport chain and uncoupling oxidative phosphorylation, which ultimately leads to neuronal bioenergetic failure. Furthermore, in certain 'at risk' areas of the brain, free radicals may induce neuronal apoptosis. In the present review, we define a role for ROS/RNS-mediated neuronal bioenergetic failure and apoptosis as a primary mechanism underlying sepsis-associated encephalopathy and, in sepsis survivors, permanent cognitive deficits.

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Calcium‐induced Cytochrome c release from CNS mitochondria is associated with the permeability transition and rupture of the outer membrane

Cited by 229 publications

References 48 publications

Morphology of mitochondrial permeability transition: Morphometric volumetry in apoptotic cells

Morphology of mitochondrial permeability transition: Morphometric volumetry in apoptotic cells

Relationships between superoxide levels and delayed calcium deregulation in cultured cerebellar granule cells exposed continuously to glutamate

Neuro-oxidative-nitrosative stress in sepsis

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