Influence of cytosolic and mitochondrial Ca2+, ATP, mitochondrial membrane potential, and calpain activity on the mechanism of neuron death induced by 3-nitropropionic acid

Nasr, Payman; Gursahani, H.; Pang, Zhen; Bondada, Vimala; Lee, Joo Young; Hadley, R. W.; Geddes, James W.

doi:10.1016/s0197-0186(02)00229-2

Cited by 72 publications

(76 citation statements)

References 52 publications

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“…As reported previously (Bizat et al, 2003;Nasr et al, 2003), 3-NP-induced cell death can involve the activation of both caspases and calpains. To examine the mechanism(s) underlying cortical neuronal degeneration induced by 3-NP, we studied the breakdown pattern of fodrin (nonerythroid a-spectrin), a sensitive substrate of both calpains and caspase-3.…”

Section: Fk506 Prevents Caspase-3 Activation In Cortical Neurons Exposupporting

confidence: 73%

“…Furthermore, the analysis of the breakdown pattern of fodrin, a sensitive substrate of both calpains and caspase-3, showed a slight accumulation of the 145-kDa calpain-mediated fodrin breakdown product only in the presence of 3 mM 3-NP. These data suggest some activation of calpains, which are normally associated with necrotic processes (Nasr et al, 2003;Pang et al, 2003).…”

Section: Discussionmentioning

confidence: 68%

“…In primary rat neuronal cultures, 3-NP induces a gradual increase in mitochondrial calcium and reactive oxygen species which are prevented in the presence of caspase inhibitors (Lee et al, 2002a). At higher concentrations, 3-NP administration results in a massive elevation of mitochondrial and cytosolic calcium, a decrease in ATP levels, a rapid mitochondrial membrane depolarization, and the activation of calpains (Lee et al, 2002b;Nasr et al, 2003;Pang and Geddes, 1997). Under these conditions, caspase activity is not affected, which is in agreement with cells undergoing death by necrosis (Nasr et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…At higher concentrations, 3-NP administration results in a massive elevation of mitochondrial and cytosolic calcium, a decrease in ATP levels, a rapid mitochondrial membrane depolarization, and the activation of calpains (Lee et al, 2002b;Nasr et al, 2003;Pang and Geddes, 1997). Under these conditions, caspase activity is not affected, which is in agreement with cells undergoing death by necrosis (Nasr et al, 2003). On the other hand, apoptotic cell death induced by 3-NP has been largely documented through the analysis of DNA fragmentation by TUNEL staining, the release of cytochrome c, the activation of caspase-3, and alterations in the levels of the apoptosis-related protein markers Bax and Bcl-2 (Kim and Chan, 2001;Rodrigues et al, 2000;Vis et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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FK506 prevents mitochondrial-dependent apoptotic cell death induced by 3-nitropropionic acid in rat primary cortical cultures

Almeida

Domingues

Rodrigues

et al. 2004

Neurobiology of Disease

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The mitochondrial toxin 3-nitropropionic acid (3-NP) has been largely used to study neurodegenerative disorders in which bioenergetic defects are implicated. In the present study, we analyzed the molecular pathways involved in FK506 neuroprotection against cell death induced by 3-NP, using cultured cortical neurons. 3-NP induced cytochrome c release and increased caspases -2, -3, -8, and -9-like activities, although, calpain activity was not significantly affected. FK506 decreased cytochrome c release and caspase-3-like activity induced by 3-NP, without changing the activities of other caspases. FK-506 also decreased the number of apoptotic neurons, determined by Hoechst. Under these conditions, FK506 alone significantly reduced calcineurin activity by about 50%. Our results also showed a decrease in mitochondrial Bax and an increase in mitochondrial Bcl-2 levels upon exposure to FK506 and 3-NP. However, no significant changes occurred in total Bcl-2 and Bax levels. Altogether, the results suggest that FK506 neuroprotection against 3-NP-induced apoptosis is associated with the redistribution of Bcl-2 and Bax in the mitochondrial membrane. D

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Section: Fk506 Prevents Caspase-3 Activation In Cortical Neurons Exposupporting

confidence: 73%

Section: Discussionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

FK506 prevents mitochondrial-dependent apoptotic cell death induced by 3-nitropropionic acid in rat primary cortical cultures

Almeida

Domingues

Rodrigues

et al. 2004

Neurobiology of Disease

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“…Only few studies have been focusing on the study of Complex II inhibition and none has provided a global assessment of subcellular Ca 2 þ signalling before cell death. These studies reported that inhibition of Complex II by 3-NP enhances basal and NMDA-induced intracellular [Ca 2 þ ] in neurons, 23,25,26 potentially leading to Dc mit loss, mitochondrial structure alteration, ROS production and cell death. 23,26,27 The parallel and thorough investigation of subcellular Ca 2 þ and bioenergetics alterations on Complex II mutation or chronic inhibition allowed us to reveal the following pattern ( Figure 8): Complex II deficiency is associated with the proteasome-dependent degradation of the two important Ca 2 þ ATPases, SERCA and PMCA thus leading to increase cytosolic Ca 2 þ signals.…”

Section: Discussionmentioning

confidence: 99%

Calcium signalling-dependent mitochondrial dysfunction and bioenergetics regulation in respiratory chain Complex II deficiency

et al. 2010

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Despite advanced knowledge on the genetic basis of oxidative phosphorylation-related diseases, the molecular and/or cellular determinants for tissue-specific dysfunction are not completely understood. Here, we report the cellular events associated with mitochondrial respiratory Complex II deficiency occurring before cell death. Mutation or chronic inhibition of Complex II determined a large increase of basal and agonist-evoked Ca 2 þ signals in the cytosol and the mitochondria, in parallel with mitochondrial dysfunction characterized by membrane potential (Dw mit ) loss, [ATP] reduction and increased reactive oxygen species production. Cytosolic and mitochondrial Ca 2 þ overload are linked to increased endoplasmic reticulum (ER) Ca 2 þ leakage, and to SERCA2b and PMCA proteasome-dependent degradation. Increased [Ca 2 þ ] mit is also contributed by decreased mitochondrial motility and increased ER-mitochondria contact sites. Interestingly, increased intracellular [Ca 2 þ ] activated on the one hand a compensatory Ca 2 þ -dependent glycolytic ATP production and determined on the second hand mitochondrial pathology. These results revealed the primary function for Ca 2 þ signalling in the control of mitochondrial dysfunction and cellular bioenergetics outcomes linked to respiratory chain Complex II deficiency. Mitochondria are the driving force behind life, as mitochondrial oxidative phosphorylation provides the main source of ATP in the cell. In addition to energy production, mitochondria have a crucial function in mediating amino-acid biosynthesis, fatty acid oxidation, intermediate metabolic pathways, free radicals production and Ca 2 þ homeostasis. 1 Mitochondria affect intracellular Ca 2 þ metabolism in two ways: (i) directly by regulating both the amplitude, duration, location and propagation of cytosolic Ca 2 þ elevations and the recycling of Ca 2 þ towards the endoplasmic reticulum (ER) and 2 (ii) indirectly by producing ATP, which is used by Ca 2 þ -dependent ATPases to pump Ca 2 þ out of the cell (by the plasma-membrane Ca 2 þ ATPase: PMCA) or into intracellular stores (by the sarco-ER Ca 2 þ ATPase: SERCA). Conversely, Ca 2 þ entering to the mitochondrial matrix regulates mitochondrial metabolism through the activation of the Ca 2 þ -dependent enzymes of the Krebs cycle. 3 Leigh's syndrome is a rare but severe and fatal encephalopathy of early childhood that is most frequently associated with deficiencies in nucleus-encoded subunits of Complex I (NDUFS3 and NDUFS7), 4,5 Complex II (SDHA), 6 Complex IV (SURF1) 7 or pyruvate dehydrogenase. 8 Despite the identification of the genetic origin of Leigh's syndrome, the molecular and cellular events associated with pathology are not completely understood.Deregulations of intracellular Ca 2 þ signalling have been reported in different models of mitochondrial respiratory chain diseases, 9-11 whereas data on Complex II deficiency are still lacking.Complex II (succinate: ubiquinone (UQ) oxidoreductase) has a central function in oxidative metabolism, being an importan...

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Acute effects of pulsed microwaves and 3‐nitropropionic acid on neuronal ultrastructure in the rat caudate‐putamen

Seaman

Phelix

2005

Bioelectromagnetics

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Ultrastructure of the medium sized "spiny" neuron in rat dorsal-lateral caudate-putamen was assessed after administration of 3-nitropropionic acid (3-NP) and exposure to pulsed microwaves. Sprague-Dawley male rats were given two daily intraperitoneal doses of 0 or 10 mg/kg 3-NP and 1.5 h after each dose were exposed to microwave radiation at a whole body averaged specific absorption rate (SAR) of 0 (sham exposure), 0.6, or 6 W/kg for 30 min. Microwave exposure consisted of 1.25 GHz radiation delivered as 5.9 micros pulses with repetition frequency 10 Hz. Tissue samples taken 2-3 h after the second sham or microwave exposure showed no injury with light microscope methods. Blinded qualitative assessment of ultrastructure of randomly selected neurons from the same samples did reveal differences. Subsequent detailed, quantitative measurements showed that, when followed by sham exposure, administration of 3-NP significantly increased endoplasmic reticulum (ER) intracisternal width, ER area density, and nuclear envelope thickness. Microwave exposure at 6 W/kg alone also significantly increased these measures. Exposure of 3-NP treated animals at 6 W/kg significantly increased effects of 3-NP on ultrastructure. Although exposure at 0.6 W/kg alone did not affect ultrastructure measures, exposure of 3-NP treated animals at 0.6 W/kg reduced the effects of 3-NP. We concluded that 3-NP changed neuronal ultrastructure and that the microwave exposures used here changed neuronal ultrastructure in ways that depended on microwave SAR and neuron metabolic status. The apparent cancellation of 3-NP induced changes by exposure to pulsed microwaves at 0.6 W/kg indicated the possibility that such exposure can protect against the effects of mitochondrial toxins on the nervous system.

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Influence of cytosolic and mitochondrial Ca2+, ATP, mitochondrial membrane potential, and calpain activity on the mechanism of neuron death induced by 3-nitropropionic acid

Cited by 72 publications

References 52 publications

FK506 prevents mitochondrial-dependent apoptotic cell death induced by 3-nitropropionic acid in rat primary cortical cultures

FK506 prevents mitochondrial-dependent apoptotic cell death induced by 3-nitropropionic acid in rat primary cortical cultures

Calcium signalling-dependent mitochondrial dysfunction and bioenergetics regulation in respiratory chain Complex II deficiency

Acute effects of pulsed microwaves and 3‐nitropropionic acid on neuronal ultrastructure in the rat caudate‐putamen

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