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

Anja Kahl, Anna Stepanova, Csaba Konrad, Corey Anderson, Giovanni Manfredi, Ping Zhou, Costantino Iadecola, Alexander Galkin

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26 Citations (Scopus)
69 Downloads (Pure)

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.

Original languageEnglish
Number of pages9
JournalStroke
Volume49
Issue number5
Early online date11 Apr 2018
DOIs
Publication statusEarly online date - 11 Apr 2018
Externally publishedYes

Keywords

  • Journal Article

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