Stepanova 2018 J Cereb Blood Flow Metab
|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].|
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:Hypoxia Organism: Rat Tissue;cell: Nervous system Preparation: Isolated mitochondria Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase
Coupling state: OXPHOS, ET Pathway: N, S, NS, ROX HRR: Oxygraph-2k, O2k-Fluorometer
Labels, 2018-09, Amplex UltraRed