Stepanova 2019 Antioxid Redox Signal
|Stepanova A, Sosunov S, Niatsetskaya Z, Konrad C, Starkov AA, Manfredi G, Wittig I, Ten V, Galkin A (2019) Redox-dependent loss of flavin by mitochondrial complex I in brain ischemia/reperfusion injury. Antioxid Redox Signal [Epub ahead of print].|
Abstract: Brain ischemia/reperfusion (I/R) is associated with impairment of mitochondrial function. However, the mechanisms of mitochondrial failure are not fully understood. This work was undertaken to determine the mechanisms and time course of mitochondrial energy dysfunction after reperfusion following neonatal brain hypoxia-ischemia (HI) in mice.
HI/reperfusion decreased the activity of mitochondrial complex I, which was recovered after 30 min of reperfusion and then declined again after 1 h. Decreased complex I activity occurred in parallel with a loss in the content of non-covalently-bound membrane flavin mononucleotide (FMN). FMN dissociation from the enzyme is caused by succinate-supported reverse electron transfer. Administration of FMN precursor riboflavin prior to HI/reperfusion was associated with decreased infarct volume, attenuation of neurological deficit and preserved complex I activity compared to vehicle-treated mice. In vitro, the rate of FMN release during oxidation of succinate was not affected by the oxygen level and amount of endogenously produced ROS.
Our data suggest that dissociation of FMN from mitochondrial complex I may represent a novel mechanism of enzyme inhibition defining respiratory chain failure in I/R. Strategies preventing FMN release during HI and reperfusion may limit the extent of energy failure and cerebral HI injury. The proposed mechanism of acute I/R-induced complex I impairment is distinct from the generally accepted mechanism of oxidative stress-mediated I/R injury.
Our study is the first to highlight a critical role of mitochondrial complex I-FMN dissociation in the development of HI-reperfusion injury of the neonatal brain.
• Keywords: Ischemia/reperfusion injury, Mitochondrial complex I, Flavin mononucleotide, Reverse electron transfer, Secondary energy failure • Bioblast editor: Plangger M • O2k-Network Lab: US NY New York Galkin A, HU Budapest Chinopoulos C
Labels: MiParea: Respiration
Stress:Ischemia-reperfusion Organism: Mouse Tissue;cell: Nervous system Preparation: Isolated mitochondria Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex IV;cytochrome c oxidase
Coupling state: LEAK, OXPHOS Pathway: N, NS HRR: Oxygraph-2k, O2k-Fluorometer
2019-05, Amplex UltraRed