Ischemia/reperfusion brain injury and flavin

Ischemia/reperfusion (I/R)-associated oxidative stress negatively affects glycolysis, the Krebs cycle, and mitochondrial energy metabolism. These are the major factors associated with brain tissue damage in I/R. However, the exact mechanisms of the so-called secondary energy failure in ischemia/reperfusion are not known. We study how brain oxygen deprivation leads to conditions in which mitochondrial complex I lose its natural cofactor, flavin mononucleotide (FMN). We identified the mechanism of flavin loss by mitochondria during brain I/R in vivo. This loss can be prevented by the administration of FMN precursor, riboflavin.

Brain I/R and the flavin of mitochondrial complex I. Under physiological conditions when oxygen is present, or normoxia, the enzyme catalyzes a physiological forward reaction of NADH oxidation by ubiquinone, supplying electrons to the rest of the respiratory chain (complexes III and IV, not shown). The succinate level is highly increased in ischemia, therefore some fraction of the enzyme is able to catalyze the reversed reaction when electrons are pushed uphill from ubiquinol towards flavin (FMN) at the nucleotide-binding site of complex I. Reverse electron transfer results in a reduction of flavin and increased generation of ROS, followed by a loss of the reduced cofactor (FMNH2), either during incomplete ischemia or at the early phase of reperfusion. FMN-deficient complex I is inactive. FMNH2 can non-enzymatically react with molecular oxygen producing ROS and oxidized flavin, which can bind back to complex I and recover enzymatic activity at a later reperfusion stage.

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