Anna Stepanova1, Sergey Sosunov1, Zoya Niatsetskaya1, Csaba Konrad2, Anatoly A Starkov2, Giovanni Manfredi2, Ilka Wittig3,4, Vadim Ten1, Alexander Galkin1. 1. 1Division of Neonatology, Department of Pediatrics, Columbia University, New York, New York. 2. 2Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York. 3. 3Functional Proteomics, SFB815 Core Unit, Medical School, Goethe University, Frankfurt, Germany. 4. 4German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, Frankfurt, Germany.
Abstract
Aims: 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. Results: 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 noncovalently bound membrane flavin mononucleotide (FMN). FMN dissociation from the enzyme is caused by succinate-supported reverse electron transfer. Administration of FMN precursor riboflavin before HI/reperfusion was associated with decreased infarct volume, attenuation of neurological deficit, and preserved complex I activity compared with 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 reactive oxygen species. Innovation: 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. Conclusion: 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. Antioxid. Redox Signal. 31, 608-622.
Aims: 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. Results: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 noncovalently bound membrane flavin mononucleotide (FMN). FMN dissociation from the enzyme is caused by succinate-supported reverse electron transfer. Administration of FMN precursor riboflavin before HI/reperfusion was associated with decreased infarct volume, attenuation of neurological deficit, and preserved complex I activity compared with 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 reactive oxygen species. Innovation: 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. Conclusion: 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. Antioxid. Redox Signal. 31, 608-622.
Entities:
Keywords:
flavin mononucleotide; ischemia/reperfusion injury; mitochondrial complex I; reverse electron transfer; secondary energy failure
Authors: Casper S Caspersen; Alexander Sosunov; Irina Utkina-Sosunova; Veniamin I Ratner; Anatoly A Starkov; Vadim S Ten Journal: Dev Neurosci Date: 2008-03-19 Impact factor: 2.984
Authors: A Lorek; Y Takei; E B Cady; J S Wyatt; J Penrice; A D Edwards; D Peebles; M Wylezinska; H Owen-Reece; V Kirkbride Journal: Pediatr Res Date: 1994-12 Impact factor: 3.756
Authors: Alexei P Kudin; Nana Yaw-B Bimpong-Buta; Stefan Vielhaber; Christian E Elger; Wolfram S Kunz Journal: J Biol Chem Date: 2003-11-18 Impact factor: 5.157
Authors: Lu Wang; Emily Thompson; Lucy Bates; Thomas L Pither; Sarah A Hosgood; Michael L Nicholson; Christopher J E Watson; Colin Wilson; Andrew J Fisher; Simi Ali; John H Dark Journal: Transplant Direct Date: 2020-08-21
Authors: Karolina Szczepanowska; Katharina Senft; Juliana Heidler; Marija Herholz; Alexandra Kukat; Michaela Nicole Höhne; Eduard Hofsetz; Christina Becker; Sophie Kaspar; Heiko Giese; Klaus Zwicker; Sergio Guerrero-Castillo; Linda Baumann; Johanna Kauppila; Anastasia Rumyantseva; Stefan Müller; Christian K Frese; Ulrich Brandt; Jan Riemer; Ilka Wittig; Aleksandra Trifunovic Journal: Nat Commun Date: 2020-04-02 Impact factor: 14.919
Authors: Andrea Schlegel; Xavier Muller; Matteo Mueller; Anna Stepanova; Philipp Kron; Olivier de Rougemont; Paolo Muiesan; Pierre-Alain Clavien; Alexander Galkin; David Meierhofer; Philipp Dutkowski Journal: EBioMedicine Date: 2020-09-24 Impact factor: 8.143
Authors: Arnau Panisello Rosello; Rui Teixeira da Silva; Carlos Castro; Raquel G Bardallo; Maria Calvo; Emma Folch-Puy; Teresa Carbonell; Carlos Palmeira; Joan Roselló Catafau; René Adam Journal: Int J Mol Sci Date: 2020-08-09 Impact factor: 5.923