Movatterモバイル変換

[0]ホーム
URL:

Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
Thehttps:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

NIH NLM Logo
Log inShow account info
Access keysNCBI HomepageMyNCBI HomepageMain ContentMain Navigation
pubmed logo
Advanced Clipboard
User Guide

Full text links

Wiley full text link Wiley Free PMC article
Full text links

Actions

Share

Review
.2008 Dec:1147:129-38.
doi: 10.1196/annals.1427.026.

Postischemic oxidative stress promotes mitochondrial metabolic failure in neurons and astrocytes

Affiliations
Review

Postischemic oxidative stress promotes mitochondrial metabolic failure in neurons and astrocytes

Gary Fiskum et al. Ann N Y Acad Sci.2008 Dec.

Abstract

Oxidative stress and mitochondrial dysfunction have been closely associated in many subcellular, cellular, animal, and human studies of both acute brain injury and neurodegenerative diseases. Our animal models of brain injury caused by cardiac arrest illustrate this relationship and demonstrate that both oxidative molecular modifications and mitochondrial metabolic impairment are exacerbated by reoxygenation of the brain using 100% ventilatory O(2) compared to lower levels that maintain normoxemia. Numerous molecular mechanisms may be responsible for mitochondrial dysfunction caused by oxidative stress, including oxidation and inactivation of mitochondrial proteins, promotion of the mitochondrial membrane permeability transition, and consumption of metabolic cofactors and intermediates, for example, NAD(H). Moreover, the relative contribution of these mechanisms to cell injury and death is likely different among different types of brain cells, for example, neurons and astrocytes. In order to better understand these oxidative stress mechanisms and their relevance to neurologic disorders, we have undertaken studies with primary cultures of astrocytes and neurons exposed to O(2) and glucose deprivation and reoxygenation and compared the results of these studies to those using a rat model of neonatal asphyxic brain injury. These results support the hypothesis that release and or consumption of mitochondrial NAD(H) is at least partially responsible for respiratory inhibition, particularly in neurons.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1. Loss of pyruvate dehydrogenase activity and matrix NAD(H) as mitochondrial mechanisms of metabolic failure
Reactive O2 and N2 species can inhibit aerobic energy metabolism and promote lactate formation in several ways, including direct inhibition of PDHC and activation of the PTP, resulting in respiratory uncoupling and loss of NAD(H), that can then be consumed by PARP-1. Acetyl-carnitine can bypass the metabolic block at PDHC. Exogenous NAD+ can enter intact mitochondria through a transporter (T), compensating for lost NAD(H), and providing the electron shuttle between dehydrogenases and the electron transport chain (ETC).
Fig. 2
Fig. 2. Inhibition of respiration by brain mitochondria after neonatal hypoxic/ischemia and reversal of inhibition by NAD+
Respiration was measured as described previously at 37°C in medium containing 5 mM glutamate and 5 mM malate as substrates in the presence of 0.8 mM ADP and the absence (A) or presence (B) of 2.5 mM NAD+. Numbers in parentheses represent rates of respiration in nmol O2/min.mg protein. ADP-stimulated (state 3) respiration was lower for mitochondria from the ipsilateral, hypoxic/ischemic hemisphere (ipsi) compared to the contralateral, hypoxia only hemisphere (contra) (A), whereas both were very similar in the presence of NAD+. Resting respiration (state 4) observed after addition of 1 μg/ml oligomycin was similar in all conditions. These tracings are representative of 7 different experiments.
Fig. 3
Fig. 3. Hyperoxic reperfusion after experimental cardiac arrest worsens mitochondrial respiration
Mitochondria were isolated from the hippocampi of dogs 2 hr after 10 min of cardiac arrest, using 1 hr of post-resuscitative mechanical ventilation on either 100% O2 (hyperoxic) or room air (21% O2; normoxic) . State 3 respiration was measured at 37°C in medium containing 0.1 mM malate plus either 5 mM pyruvate or 5 mM glutamate, as described previously. Values represent the means ± SEM for 4 separate experiments. * Significantly different than non-ischemic, sham-operated controls; 1-way ANOVA with Tukey post hoc analysis, p < 0.05.
Fig. 4
Fig. 4. Hyperoxia promotes death of astrocytes and neurons during rexoygenation after exposure to O2 and glucose deprivation (OGD)
Rat cortical astrocytes (10 DIV) or murine hippocampal neurons (6 DIV) were exposed to OGD 4 hr and 0.5 hr, respectively, in serum-free “ischemic salts solution”, as described previously . The medium was then replaced with serum-free normal growth medium and the cells exposed to either 20% or 7% ambient O2. Cell death was measured 24 hr later using the Hoescht/propidium iodide fluorescent assay for astrocytes and the Live/Dead Assay (Invitrogen) for neurons. See Danilov and Fiskum for additional details. Values represent the means ± SEM for 6 - 8 separate experiments. * Significantly different from 20% O2; t test, p < 0.05.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. BLOMGREN K, HAGBERG H. Free radicals, mitochondria, and hypoxia-ischemia in the developing brain. Free Radic. Biol. Med. 2006;40:388–397. - PubMed
    1. FISKUM G, MURPHY AN, BEAL MF. Mitochondria in neurodegeneration: acute ischemia and chronic neurodegenerative diseases. J. Cereb. Blood Flow Metab. 1999;19:351–369. - PubMed
    1. RIZZUTO R, SIMPSON AW, BRINI M, POZZAN T. Rapid changes of mitochondrial Ca2+ revealed by specifically targeted recombinant aequorin. Nature. 1992;358:325–327. [published erratum appears in Nature 1992 Dec 24- 31;360(6406):768] - PubMed
    1. CHANG LH, SHIMIZU H, ABIKO H, SWANSON RA, FADEN AI, JAMES TL, WEINSTEIN PR. Effect of dichloroacetate on recovery of brain lactate, phosphorus energy metabolites, and glutamate during reperfusion after complete cerebral ischemia in rats. J. Cereb. Blood Flow Metab. 1992;12:1030–1038. - PubMed
    1. KURODA S, KATSURA KI, TSUCHIDATE R, SIESJO BK. Secondary bioenergetic failure after transient focal ischaemia is due to mitochondrial injury. Acta Physiol. Scand. 1996;156:149–150. - PubMed

Publication types

MeSH terms

Related information

Grants and funding

LinkOut - more resources

Full text links
Wiley full text link Wiley Free PMC article
Cite
Send To

NCBI Literature Resources

MeSHPMCBookshelfDisclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

[8]ページ先頭
©2009-2025 Movatter.jp