Deactivation of mitochondrial complex I after hypoxia–ischemia in the immature brain

Author:

Stepanova Anna12,Konrad Csaba2,Guerrero-Castillo Sergio3,Manfredi Giovanni2,Vannucci Susan4,Arnold Susanne3,Galkin Alexander12ORCID

Affiliation:

1. School of Biological Sciences, Queen's University Belfast, Medical Biology Centre, Belfast, UK

2. Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA

3. Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

4. Department of Pediatrics/Newborn Medicine, Weill Cornell Medicine, New York, NY, USA

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.

Publisher

SAGE Publications

Subject

Cardiology and Cardiovascular Medicine,Clinical Neurology,Neurology

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