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Mitochondrial Dysfunction and NAD+ Metabolism Alterations in the Pathophysiology of Acute Brain Injury

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Abstract

Mitochondrial dysfunction is commonly believed to be one of the major players in mechanisms of brain injury. For several decades, pathologic mitochondrial calcium overload and associated opening of the mitochondrial permeability transition (MPT) pore were considered a detrimental factor causing mitochondrial damage and bioenergetics failure. Mitochondrial and cellular bioenergetic metabolism depends on the enzymatic reactions that require NAD+ or its reduced form NADH as cofactors. Recently, it was shown that NAD+ also has an important function as a substrate for several NAD+ glycohydrolases whose overactivation can contribute to cell death mechanisms. Furthermore, downstream metabolites of NAD+ catabolism can also adversely affect cell viability. In contrast to the negative effects of NAD+-catabolizing enzymes, enzymes that constitute the NAD+ biosynthesis pathway possess neuroprotective properties. In the first part of this review, we discuss the role of MPT in acute brain injury and its role in mitochondrial NAD+ metabolism. Next, we focus on individual NAD+ glycohydrolases, both cytosolic and mitochondrial, and their role in NAD+ catabolism and brain damage. Finally, we discuss the potential effects of downstream products of NAD+ degradation and associated enzymes as well as the role of NAD+ resynthesis enzymes as potential therapeutic targets.

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Acknowledgments

This work was supported by US Veterans Affairs Merit Grant BX000917 to TK.

Conflict of Interest

Katrina Owens, Ji H. Park, Rosemary Schuh, and Tibor Kristian declare that they have no conflicts of interest. This article does not contain any studies with human or animal subjects.

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Authors and Affiliations

  1. Veterans Affairs Maryland Health Care System, 10 North Greene Street, Baltimore, MD, 21201, USA

    Katrina Owens, Ji H. Park, Rosemary Schuh & Tibor Kristian

  2. Department of Anesthesiology, Center for Shock, Trauma and Anesthesiology Research, School of Medicine, University of Maryland, Baltimore, 685 West Baltimore Street, MSTF 534, Baltimore, MD, 21201, USA

    Tibor Kristian

  3. Department of Neurology, School of Medicine, University of Maryland, Baltimore, Baltimore, MD, USA

    Rosemary Schuh

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  1. Katrina Owens
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  2. Ji H. Park
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Correspondence to Tibor Kristian.

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Owens, K., Park, J.H., Schuh, R. et al. Mitochondrial Dysfunction and NAD+ Metabolism Alterations in the Pathophysiology of Acute Brain Injury. Transl. Stroke Res. 4, 618–634 (2013). https://doi.org/10.1007/s12975-013-0278-x

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