期刊
STROKE
卷 49, 期 5, 页码 1223-+出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/STROKEAHA.117.019687
关键词
flavin mononucleotide; glutathione; mitochondria; oxidative stress; reperfusion
资金
- Medical Research Council UK [MR/L007339/1]
- National Institutes of Health [R01NS34179, R01NS095692]
- Deutsche Forschungsgemeinschaft [KA3810/1-1]
- MRC [MR/L007339/1] Funding Source: UKRI
- Medical Research Council [MR/L007339/1] Funding Source: researchfish
Background and Purpose-Ischemic brain injury is characterized by 2 temporally distinct but interrelated phases: ischemia (primary energy failure) and reperfusion (secondary energy failure). Loss of cerebral blood flow leads to decreased oxygen levels and energy crisis in the ischemic area, initiating a sequence of pathophysiological events that after reoxygenation lead to ischemia/reperfusion (I/R) brain damage. Mitochondrial impairment and oxidative stress are known to be early events in I/R injury. However, the biochemical mechanisms of mitochondria damage in I/R are not completely understood. Methods-We used a mouse model of transient focal cerebral ischemia to investigate acute I/R-induced changes of mitochondrial function, focusing on mechanisms of primary and secondary energy failure. Results-Ischemia induced a reversible loss of flavin mononucleotide from mitochondrial complex I leading to a transient decrease in its enzymatic activity, which is rapidly reversed on reoxygenation. Reestablishing blood flow led to a reversible oxidative modification of mitochondrial complex I thiol residues and inhibition of the enzyme. Administration of glutathione-ethyl ester at the onset of reperfusion prevented the decline of complex I activity and was associated with smaller infarct size and improved neurological outcome, suggesting that decreased oxidation of complex I thiols during I/R-induced oxidative stress may contribute to the neuroprotective effect of glutathione ester. Conclusions-Our results unveil a key role of mitochondrial complex I in the development of I/R brain injury and provide the mechanistic basis for the well-established mitochondrial dysfunction caused by I/R. Targeting the functional integrity of complex I in the early phase of reperfusion may provide a novel therapeutic strategy to prevent tissue injury after stroke. Visual Overview-An online visual overview is available for this article.
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