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

J Cereb Blood Flow Metab. 2019 Sep;39(9):1790-1802. doi: 10.1177/0271678X18770331. Epub 2018 Apr 9.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Brain / metabolism
  • Brain / pathology
  • Cells, Cultured
  • Electron Transport
  • Electron Transport Complex I / metabolism*
  • Female
  • Humans
  • Hydrogen Peroxide / metabolism
  • Hypoxia-Ischemia, Brain / metabolism*
  • Hypoxia-Ischemia, Brain / pathology
  • Male
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Rats, Wistar
  • Reactive Oxygen Species / metabolism


  • Reactive Oxygen Species
  • Hydrogen Peroxide
  • Electron Transport Complex I