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Biochim Biophys Acta. 2016 Jul;1857(7):946-57. doi: 10.1016/j.bbabio.2015.12.013. Epub 2016 Jan 9.

Ischemic A/D transition of mitochondrial complex I and its role in ROS generation.

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Clinic of Anesthesiology, Intensive-Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main 60590, Germany. Electronic address:
Medical Biology Centre, School of Biological Sciences, Queens University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.
Medical Biology Centre, School of Biological Sciences, Queens University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK; Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, 407 East 61st Street, New York, NY 10065, USA. Electronic address:


Mitochondrial complex I (NADH:ubiquinone oxidoreductase) is a key enzyme in cellular energy metabolism and provides approximately 40% of the proton-motive force that is utilized during mitochondrial ATP production. The dysregulation of complex I function--either genetically, pharmacologically, or metabolically induced--has severe pathophysiological consequences that often involve an imbalance in the production of reactive oxygen species (ROS). Slow transition of the active (A) enzyme to the deactive, dormant (D) form takes place during ischemia in metabolically active organs such as the heart and brain. The reactivation of complex I occurs upon reoxygenation of ischemic tissue, a process that is usually accompanied by an increase in cellular ROS production. Complex I in the D-form serves as a protective mechanism preventing the oxidative burst upon reperfusion. Conversely, however, the D-form is more vulnerable to oxidative/nitrosative damage. Understanding the so-called active/deactive (A/D) transition may contribute to the development of new therapeutic interventions for conditions like stroke, cardiac infarction, and other ischemia-associated pathologies. In this review, we summarize current knowledge on the mechanism of A/D transition of mitochondrial complex I considering recently available structural data and site-specific labeling experiments. In addition, this review discusses in detail the impact of the A/D transition on ROS production by complex I and the S-nitrosation of a critical cysteine residue of subunit ND3 as a strategy to prevent oxidative damage and tissue damage during ischemia-reperfusion injury. This article is part of a Special Issue entitled Respiratory complex I, edited by Volker Zickermann and Ulrich Brandt.


A/D transition; Ischemia/reperfusion injury; Mitochondrial complex I; ROS generation; Thiol redox modification

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