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Molecular Mechanisms of Ischemia–Reperfusion Injury in Brain: Pivotal Role of the Mitochondrial Membrane Potential in Reactive Oxygen Species Generation

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Abstract

Stroke and circulatory arrest cause interferences in blood flow to the brain that result in considerable tissue damage. The primary method to reduce or prevent neurologic damage to patients suffering from brain ischemia is prompt restoration of blood flow to the ischemic tissue. However, paradoxically, restoration of blood flow causes additional damage and exacerbates neurocognitive deficits among patients who suffer a brain ischemic event. Mitochondria play a critical role in reperfusion injury by producing excessive reactive oxygen species (ROS) thereby damaging cellular components, and initiating cell death. In this review, we summarize our current understanding of the mechanisms of mitochondrial ROS generation during reperfusion, and specifically, the role the mitochondrial membrane potential plays in the pathology of cerebral ischemia/reperfusion. Additionally, we propose a temporal model of ROS generation in which posttranslational modifications of key oxidative phosphorylation (OxPhos) proteins caused by ischemia induce a hyperactive state upon reintroduction of oxygen. Hyperactive OxPhos generates high mitochondrial membrane potentials, a condition known to generate excessive ROS. Such a state would lead to a “burst” of ROS upon reperfusion, thereby causing structural and functional damage to the mitochondria and inducing cell death signaling that eventually culminate in tissue damage. Finally, we propose that strategies aimed at modulating this maladaptive hyperpolarization of the mitochondrial membrane potential may be a novel therapeutic intervention and present specific studies demonstrating the cytoprotective effect of this treatment modality.

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Acknowledgments

This work was supported by the Department of Emergency Medicine, the Cardiovascular Research Institute, Wayne State University, Detroit, and grant GM089900 from the National Institutes of Health.

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Authors and Affiliations

  1. Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Thomas H. Sanderson, Christian A. Reynolds, Rita Kumar, Karin Przyklenk & Maik Hüttemann

  2. Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Thomas H. Sanderson, Christian A. Reynolds, Rita Kumar & Karin Przyklenk

  3. Department of Physiology, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Thomas H. Sanderson, Christian A. Reynolds, Rita Kumar & Karin Przyklenk

  4. Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Maik Hüttemann

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Sanderson, T.H., Reynolds, C.A., Kumar, R. et al. Molecular Mechanisms of Ischemia–Reperfusion Injury in Brain: Pivotal Role of the Mitochondrial Membrane Potential in Reactive Oxygen Species Generation. Mol Neurobiol 47, 9–23 (2013). https://doi.org/10.1007/s12035-012-8344-z

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