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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / metabolism*
  • Brain Ischemia / metabolism
  • Cerebrovascular Circulation
  • Citrate (si)-Synthase / drug effects
  • Citrate (si)-Synthase / metabolism
  • Disease Models, Animal
  • Electron Transport Complex I / drug effects
  • Electron Transport Complex I / metabolism*
  • Energy Metabolism
  • Flavin Mononucleotide / metabolism*
  • Glutathione / analogs & derivatives
  • Glutathione / metabolism*
  • Glutathione / pharmacology
  • Infarction, Middle Cerebral Artery / metabolism*
  • Male
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Oxidative Stress / drug effects
  • Random Allocation
  • Reperfusion Injury / metabolism*
  • Sulfhydryl Compounds / metabolism


  • Sulfhydryl Compounds
  • Flavin Mononucleotide
  • S-ethyl glutathione
  • Citrate (si)-Synthase
  • Electron Transport Complex I
  • Glutathione