Mitochondrial calcium and oxidative stress as mediators of ischemic brain injury

Starkov, Anatoly A.; Chinopoulos, Christos; Fiskum, Gary

doi:10.1016/j.ceca.2004.02.012

Cited by 306 publications

(233 citation statements)

References 131 publications

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“…In fact, within 15 to 60 minutes following SCI, the intracellular concentrations of sodium, chloride, and calcium (Ca 2+ ) increase, whereas the intracellular concentrations of potassium and magnesium decrease [14]. Mitochondria can function as Ca 2+ "sinks," taking up the excess Ca 2+ to maintain homeostatic levels of Ca 2+ within the cytosol [15][16][17][18]. However, the principle trigger for opening the mitochondrial permeability transition pore (mPTP) in the mitochondrial inner membrane is mitochondrial matrix Ca 2+ in the presence of phosphate.…”

Section: Mitochondrial Permeability Transition Porementioning

confidence: 99%

“…As a consequence, these oxyradicals accumulate and contribute to the formation of lipid peroxidation, protein oxidation, and peroxynitrite byproducts that interact with and inactivate critical mitochondrial enzyme complexes. One approach to combat the increase in free radical accumulation is to develop modified antioxidants that target the mitochondrial matrix, where these oxyradicals are produced [18,[58][59][60]. A separate review dedicated to antioxidant treatment in acute SCI is included in this issue and the reader is referred the accompanying review by Hall et al for details.…”

Section: Development Of Antioxidant Strategies Designed To Target Mitmentioning

confidence: 99%

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Targeting Mitochondrial Function for the Treatment of Acute Spinal Cord Injury

et al. 2011

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Summary: Traumatic injury to the mammalian spinal cord is a highly dynamic process characterized by a complex pattern of pervasive and destructive biochemical and pathophysiological events that limit the potential for functional recovery. Currently, there are no effective therapies for the treatment of spinal cord injury (SCI) and this is due, in part, to the widespread impact of the secondary injury cascades, including edema, ischemia, excitotoxicity, inflammation, oxidative damage, and activation of necrotic and apoptotic cell death signaling events. In addition, many of the signaling pathways associated with these cascades intersect and initiate other secondary injury events. Therefore, it can be argued that therapeutic strategies targeting a specific biochemical cascade may not provide the best approach for promoting functional recovery. A "systems approach" at the subcellular level may provide a better strategy for promoting cell survival and function and, as a consequence, improve functional outcomes following SCI. One such approach is to study the impact of SCI on the biology and function of mitochondria, which serve a major role in cellular bioenergetics, function, and survival. In this review, we will briefly describe the importance and unique properties of mitochondria in the spinal cord, and what is known about the response of mitochondria to SCI. We will also discuss a number of strategies with the potential to promote mitochondrial function following SCI.

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Section: Mitochondrial Permeability Transition Porementioning

confidence: 99%

Section: Development Of Antioxidant Strategies Designed To Target Mitmentioning

confidence: 99%

Targeting Mitochondrial Function for the Treatment of Acute Spinal Cord Injury

et al. 2011

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“…This enabled evaluation of a wide range of mPT inhibition by the cyclosporin analogs. Analogs 1-15 (identity given in Table 1) were evaluated in both mouse brain and mouse liver mitochondria, analogs [16][17][18][19] in mouse liver mitochondria only and NIM811 and UNIL025 (renamed DEBIO-025) were evaluated previously in rat brain mitochondria [28]. To enable inter-experimental comparisons of all analogs their relative inhibition of calcium-induced mPT was compared to that of CsA, all at 1 µM.…”

Section: Mitochondrial Light Scattering and Swellingmentioning

confidence: 99%

“…Increased ROS production from mitochondria has been demonstrated following NMDA receptor stimulation in models of excitotoxicity and has also been coupled to mitochondrial loading of calcium [10][11][12][13][14][15]. However, the mechanism linking mitochondrial calcium loading and ROS production is currently unresolved [15][16][17], and studies in isolated brain mitochondria have yielded diverging results regarding the effect of calcium on mitochondrial ROS generation [18][19][20][21][22]. Mitochondria are able to buffer cellular calcium transients and have high capacity for calcium retention under normal physiological conditions [23].…”

Section: Introductionmentioning

confidence: 99%

Calcium-induced generation of reactive oxygen species in brain mitochondria is mediated by permeability transition

Hansson

Månsson

Morota

et al. 2008

Free Radical Biology and Medicine

110

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Mitochondrial uptake of calcium in excitotoxicity is associated with subsequent increase in reactive oxygen species (ROS) generation and delayed cellular calcium deregulation in ischemic and neurodegenerative insults. The mechanisms linking mitochondrial calcium uptake and ROS production remain unknown but activation of the mitochondrial permeability transition (mPT) may be one such mechanism. In the present study, calcium increased ROS generation in isolated rodent brain and human liver mitochondria undergoing mPT despite an associated loss of membrane potential, NADH and respiration. Unspecific permeabilization of the inner mitochondrial membrane by alamethicin likewise increased ROS independently of calcium, and the ROS increase was further potentiated if NAD(H) was added to the system. Importantly, calcium per se did not induce a ROS increase unless mPT was triggered. Twenty-one cyclosporin A analogs were evaluated for inhibition of calcium-induced ROS and their efficacy clearly paralleled their potency of inhibiting mPT-mediated mitochondrial swelling. We conclude that while intact respiring mitochondria possess powerful antioxidant capability, mPT induces a dysregulated oxidative state with loss of GSH-and NADPH-dependent ROS detoxification. We propose that mPT is a significant cause of pathological ROS generation in excitotoxic cell death.

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“…These conditions, which are required for the activation of PT, develop in neuronal cell cultures subjected to oxidative stress, excitotoxicity, and oxygen-glucose deprivation. In these settings, the sequestration of high levels of calcium by mitochondria is suggested to be the underlying cause of cell death (21,22). In vivo parameters required for the induction of PT are mimicked during ischemia͞reperfusion in the brain.…”

mentioning

confidence: 99%

Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia

Schinzel

Takeuchi²,

Huang³

et al. 2005

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

760

650

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Mitochondrial permeability transition (PT) is a phenomenon induced by high levels of matrix calcium and is characterized by the opening of the PT pore (PTP). Activation of the PTP results in loss of mitochondrial membrane potential, expansion of the matrix, and rupture of the mitochondrial outer membrane. Consequently, PT has been implicated in both apoptotic and necrotic cell death. Cyclophilin D (CypD) appears to be a critical component of the PTP. To investigate the role of CypD in cell death, we created a CypD-deficient mouse. In vitro, CypD-deficient mitochondria showed an increased capacity to retain calcium and were no longer susceptible to PT induced by the addition of calcium. CypD-deficient primary mouse embryonic fibroblasts (MEFs) were as susceptible to classical apoptotic stimuli as the WT, suggesting that CypD is not a central component of cell death in response to these specific death stimuli. However, CypD-deficient MEFs were significantly less susceptible than their WT counterparts to cell death induced by hydrogen peroxide, implicating CypD in oxidative stress-induced cell death. Importantly, CypD-deficient mice displayed a dramatic reduction in brain infarct size after acute middle cerebral artery occlusion and reperfusion, strongly supporting an essential role for CypD in an ischemic injury model in which calcium overload and oxidative stress have been implicated. mitochondria ͉ oxidative stress ͉ calcium homeostasis N umerous toxic stimuli convert mitochondria from a lifesustaining organelle to an inducer of cell death (1-3). In response to cell death stimuli, prodeath proteins sequestered in the inner mitochondrial membrane space are released into the cytosol upon disruption of the mitochondrial outer membrane (MOM) (4-6). The proapoptotic BCL-2 family members BAX and BAK constitute a ''gateway'' to the apoptotic program by regulating events leading to disruption of the MOM (7). BCL-2 family members not only function at the MOM but also are located at the endoplasmic reticulum (ER), where they regulate calcium fluxes. By controlling steady-state calcium levels in the ER, BCL-2 family members regulate the amount of calcium released from the ER to transmit a death signal mediated by mitochondrial calcium uptake (8-11).Sequestration of high levels of calcium by mitochondria can also lead to disruption of the MOM, which, mechanistically, is thought to occur by means of the phenomenon of permeability transition (PT). PT is described as an abrupt increase of inner membrane permeability to solutes with molecular masses of Ͻ1,500 Da. These events are caused by the opening of a highly regulated channel [PT pore (PTP)], which leads to dissipation of the mitochondrial transmembrane potential and an influx of solutes, causing expansion of the matrix (reviewed in ref. 12). The latter event may result in sufficient swelling to rupture the MOM and cause cytochrome c release and subsequent caspase activation, resulting in apoptosis. However, dissipation of the membrane potential can also lead to a sudden d...

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Mitochondrial calcium and oxidative stress as mediators of ischemic brain injury

Cited by 306 publications

References 131 publications

Targeting Mitochondrial Function for the Treatment of Acute Spinal Cord Injury

Targeting Mitochondrial Function for the Treatment of Acute Spinal Cord Injury

Calcium-induced generation of reactive oxygen species in brain mitochondria is mediated by permeability transition

Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia

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