Format

Send to

Choose Destination
J Cereb Blood Flow Metab. 2018 Apr 9:271678X18770331. doi: 10.1177/0271678X18770331. [Epub ahead of print]

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

Author information

1
1 School of Biological Sciences, 1596 Queen's University Belfast , Medical Biology Centre, Belfast, UK.
2
2 Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
3
3 Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
4
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.

KEYWORDS:

A/D transition; Ischemia; immature brain; mitochondrial complex I; reactive oxygen species

PMID:
29629602
DOI:
10.1177/0271678X18770331

Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center