flavin-mononucleotide and Ischemia

Pathologies associated with tissue ischemia/reperfusion (I/R) in highly metabolizing organs such as the brain and heart are leading causes of death and disability in humans. Molecular mechanisms underlying mitochondrial dysfunction during acute injury in I/R are tissue-specific, but their details are not completely understood. A metabolic shift and accumulation of substrates of reverse electron transfer (RET) such as succinate are observed in tissue ischemia, making mitochondrial complex I of the respiratory chain (NADH:ubiquinone oxidoreductase) the most vulnerable enzyme to the following reperfusion. It has been shown that brain complex I is predisposed to losing its flavin mononucleotide (FMN) cofactor when maintained in the reduced state in conditions of RET both in vitro and in vivo. Here we investigated the process of redox-dependent dissociation of FMN from mitochondrial complex I in brain and heart mitochondria. In contrast to the brain enzyme, cardiac complex I does not lose FMN when reduced in RET conditions. We proposed that the different kinetics of FMN loss during RET is due to the presence of brain-specific long 50 kDa isoform of the NDUFV3 subunit of complex I, which is absent in the heart where only the canonical 10 kDa short isoform is found. Our simulation studies suggest that the long NDUFV3 isoform can reach toward the FMN binding pocket and affect the nucleotide affinity to the apoenzyme. For the first time, we demonstrated a potential functional role of tissue-specific isoforms of complex I, providing the distinct molecular mechanism of I/R-induced mitochondrial impairment in cardiac and cerebral tissues. By combining functional studies of intact complex I and molecular structure simulations, we defined the critical difference between the brain and heart enzyme and suggested insights into the redox-dependent inactivation mechanisms of complex I during I/R injury in both tissues.

Topics: Brain; Dinitrocresols; Electron Transport Complex I; Flavin Mononucleotide; Heart; Humans; Ischemia; Mitochondria, Heart; Oxidation-Reduction

Experiments on Wistar rats showed the development of endotoxicosis 12 h after severe compression injury. Endotoxicosis manifested in disorders in bromosulfaleine excretion from the blood, increase of blood urea, uric acid, creatinine, and potassium levels and aminotransferase activities. Injection of succinate-containing antihypoxants (reamberine, cytoflavin, metaprot plus, succinamic acid 2-amino-4-acetylthiasolo[5,4-b]indole) directly after decompression promoted recovery of liver function, prevented the development of hyperfermentemia and renal failure as a result of reduced blood levels of potassium and non-protein nitrogen. The protective effect of the drugs in traumatic toxicosisdecreased in the following order: metaprot plus>cytoflavin>2-amino-4-acetylthiasolo[5,4-b]indole succinaminic acid>reamberine.

Topics: Animals; Antioxidants; Drug Combinations; Endotoxemia; Flavin Mononucleotide; Inosine Diphosphate; Ischemia; Male; Meglumine; Niacinamide; Nitrogen; Potassium; Rats; Rats, Wistar; Succinates