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Kahl 2018 Stroke

From Bioblast
Publications in the MiPMap
Kahl A, Stepanova A, Konrad C, Anderson C, Manfredi G, Zhou P, Iadecola C, Galkin A (2018) Critical role of flavin and glutathione in complex I-mediated bioenergetic failure in brain ischemia/reperfusion injury. Stroke 49:1223-31.

Β» PMID: 29643256 Open Access

Kahl A, Stepanova A, Konrad C, Anderson C, Manfredi G, Zhou P, Iadecola C, Galkin A (2018) Stroke

Abstract: 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.

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.

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.

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.

Β© 2018 The Authors. β€’ Keywords: Flavin mononucleotide, Glutathione, Mitochondria, Oxidative stress, Reperfusion β€’ Bioblast editor: Plangger M β€’ 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: Homogenate  Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase 

Coupling state: LEAK, OXPHOS  Pathway: CIV  HRR: Oxygraph-2k 

Labels, 2018-09