Stepanova 2018 J Cereb Blood Flow Metab

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Stepanova A, Konrad C, Guerrero-Castillo S, Manfredi G, Vannucci S, Arnold S, Galkin A (2018) Deactivation of mitochondrial complex I after hypoxia-ischemia in the immature brain. J Cereb Blood Flow Metab [Epub ahead of print].

» PMID: 29629602

Stepanova A, Konrad C, Guerrero-Castillo S, Manfredi G, Vannucci S, Arnold S, Galkin A (2018) J Cereb Blood Flow Metab

Abstract: Mortality from perinatal hypoxic-ischemic (HI) brain injury reached 1.15 million worldwide in 2010 and is also a major factor for neurological disability in infants. HI directly influences the oxidative phosphorylation enzyme complexes in mitochondria, but the exact mechanism of HI-reoxygenation response in brain remains largely unresolved. After induction of HI-reoxygenation in postnatal day 10 rats, activities of mitochondrial respiratory chain enzymes were analysed and complexome profiling was performed. The effect of conformational state (active/deactive (A/D) transition) of mitochondrial complex I on H2O2 release was measured simultaneously with mitochondrial oxygen consumption. In contrast to cytochrome c oxidase and succinate dehydrogenase, HI-reoxygenation resulted in inhibition of mitochondrial complex I at 4 h after reoxygenation. Immediately after HI, we observed a robust increase in the content of deactive (D) form of complex I. The D-form is less active in reactive oxygen species (ROS) production via reversed electron transfer, indicating the key role of the deactivation of complex I in ischemia/reoxygenation. We describe a novel mechanism of mitochondrial response to ischemia in the immature brain. HI induced a deactivation of complex I in order to reduce ROS production following reoxygenation. Delayed activation of complex I represents a novel mitochondrial target for pathological-activated therapy.

Keywords: A/D transition, Ischemia, Immature brain, Mitochondrial complex I, Reactive oxygen species Bioblast editor: Plangger M O2k-Network Lab: US NY New York Galkin A, HU Budapest Chinopoulos C

Labels: MiParea: Respiration 

Stress:Ischemia-reperfusion, Hypoxia  Organism: Rat  Tissue;cell: Nervous system  Preparation: Isolated mitochondria  Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Supercomplex  Regulation: Oxygen kinetics  Coupling state: LEAK, OXPHOS, ET  Pathway: N, S, ROX  HRR: Oxygraph-2k, O2k-Fluorometer 

2018-09, Amplex UltraRed