Kim 2018 Free Radic Biol Med

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Kim M, Stepanova A, Niatsetskaya Z, Sosunov S, Arndt S, Murphy MP, Galkin A, Ten VS (2018) Attenuation of oxidative damage by targeting mitochondrial complex I in neonatal hypoxic-ischemic brain injury. Free Radic Biol Med 124:517-24.

» PMID: 30037775 Open Access

Kim M, Stepanova A, Niatsetskaya Z, Sosunov S, Arndt S, Murphy MP, Galkin A, Ten VS (2018) Free Radic Biol Med

Abstract: Establishing sustained reoxygenation/reperfusion ensures not only the recovery, but may initiate a reperfusion injury in which oxidative stress plays a major role. This study offers the mechanism and this mechanism-specific therapeutic strategy against excessive release of reactive oxygen species (ROS) associated with reperfusion-driven recovery of mitochondrial metabolism.

In neonatal mice subjected to cerebral hypoxia-ischaemia (HI) and reperfusion, we examined conformational changes and activity of mitochondrial complex I with and without post-HI administration of S-nitrosating agent, MitoSNO. Assessment of mitochondrial ROS production, oxidative brain damage, neuropathological and neurofunctional outcomes were used to define neuroprotective strength of MitoSNO. A specificity of reperfusion-driven mitochondrial ROS production to conformational changes in complex I was examined in vitro.

HI deactivated complex I, changing its conformation from active form (A) into the catalytically dormant, de-active form (D). Reperfusion rapidly converted the D-form into the A-form and increased ROS generation. Administration of MitoSNO at the onset of reperfusion, decelerated D→A transition of complex I, attenuated oxidative stress, and significantly improved neurological recovery. In cultured neurons, after simulated ischaemia-reperfusion injury, MitoSNO significantly reduced ROS generation and neuronal mortality. In isolated mitochondria subjected to anoxia-reoxygenation, MitoSNO restricted ROS release during D→A transitions.

Rapid D→A conformation in response to reperfusion reactivates complex I. This is essential not only for metabolic recovery, but also contributes to excessive release of mitochondrial ROS and reperfusion injury. We propose that the initiation of reperfusion should be followed by pharmacologically-controlled gradual reactivation of complex I.

Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Keywords: Hypoxia/ischaemia, Ischaemia/reperfusion damage, Mitochondrial complex I, Nitrosation Bioblast editor: Plangger M O2k-Network Lab: US NY New York Galkin A


Labels: MiParea: Respiration, Pharmacology;toxicology 

Stress:Ischemia-reperfusion, Hypoxia  Organism: Mouse  Tissue;cell: Nervous system  Preparation: Isolated mitochondria  Enzyme: Complex I 

Coupling state: OXPHOS  Pathway: N, S  HRR: Oxygraph-2k, O2k-Fluorometer 

Labels, 2018-09, Amplex UltraRed