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Biochemistry (Moscow)

, Volume 84, Issue 11, pp 1411–1423 | Cite as

Brain Ischemia/Reperfusion Injury and Mitochondrial Complex I Damage

  • A. GalkinEmail author
Review
  • 35 Downloads

Abstract

Ischemic stroke and neonatal hypoxic-ischemic encephalopathy are two of the leading causes of disability in adults and infants. The energy demands of the brain are provided by mitochondrial oxidative phosphorylation. Ischemia/reperfusion (I/R) affects the production of ATP in brain mitochondria, leading to energy failure and death of the affected tissue. Among the enzymes of the mitochondrial respiratory chain, mitochondrial complex I is the most sensitive to I/R; however, the mechanisms of its inhibition are poorly understood. This article reviews some of the existing data on the mitochondria impairment during I/R and proposes two distinct mechanisms of complex I damage emerging from recent studies. One mechanism is a reversible dissociation of natural flavin mononucleotide cofactor from the enzyme I after ischemia. Another mechanism is a modification of critical cysteine residue of complex I involved into the active/deactive conformational transition of the enzyme. I describe potential effects of these two processes in the development of mitochondrial I/R injury and briefly discuss possible neuroprotective strategies to ameliorate I/R brain injury.

Keywords

stroke ischemia-reperfusion injury mitochondria complex I flavin thiols nitrosation 

Abbriviation

A/D transition

active/deactive transition

FAD

flavin adenine dinucleotide

FMN/FMNH2

oxidized/reduced flavin mononucleotide

HI

hypoxia-ischemia

I/R

ischemia/reperfusion

MCAO

middle cerebral artery occlusion

Q

ubiquinone

RET

reverse electron transfer

ROS

reactive oxygen species

TCA

tricarboxylic acid (cycle)

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Notes

Acknowledgements

I am grateful to Dr. Anna Stepanova and Dr. Vadim Ten for critical reading of the manuscript. I also wish to thank Dr. Vera Grivennikova for the help with the Russian version of this review and valuable discussions. Thanks are due to Nicole Sayles for her help in the preparation of the review.

Funding

The work in the author’s laboratory was supported by the NIH grant NS-100850 and MRC UK grants G1100051 and MR/L007339/1.

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© Pleiades Publishing, Ltd. 2019

Authors and Affiliations

  1. 1.Division of Neonatology, Department of PediatricsColumbia University William Black Building, NYNew YorkUSA

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