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Stroke. 2018 May;49(5):1223-1231. doi: 10.1161/STROKEAHA.117.019687. Epub 2018 Apr 11.

Critical Role of Flavin and Glutathione in Complex I-Mediated Bioenergetic Failure in Brain Ischemia/Reperfusion Injury.

Author information

1
From the Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY (A.K., A.S., C.K., C.A., G.M., P.Z., C.I., A.G.).
2
School of Biological Sciences, Queen's University Belfast, United Kingdom (A.S., A.G.).

Abstract

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.

KEYWORDS:

flavin mononucleotide; glutathione; mitochondria; oxidative stress; reperfusion

PMID:
29643256
PMCID:
PMC5916474
DOI:
10.1161/STROKEAHA.117.019687
[Indexed for MEDLINE]
Free PMC Article

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