REVIEW: Brain Ischemia/Reperfusion Injury and Mitochondrial Complex I Damage

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A. Galkin^a

Division of Neonatology, Department of Pediatrics, Columbia University William Black Building, NY 10032, New York, USA

Received June 7, 2019; Revised July 8, 2019; Accepted July 9, 2019

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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.

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KEY WORDS: stroke, ischemia-reperfusion injury, mitochondria, complex I, flavin, thiols, nitrosation

DOI: 10.1134/S0006297919110154

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