Article

Mitochondrial dysfunction and nicotinamide dinucleotide catabolism as mechanisms of cell death and promising targets for neuroprotection

Department of Anesthesiology, Center for Shock, Trauma and Anesthesiology Research, School of Medicine, University of Maryland Baltimore, Baltimore, Maryland 21201, USA.
Journal of Neuroscience Research (Impact Factor: 2.59). 12/2011; 89(12):1946-55. DOI: 10.1002/jnr.22626
Source: PubMed

ABSTRACT

Both acute and chronic neurodegenerative diseases are frequently associated with mitochondrial dysfunction as an essential component of mechanisms leading to brain damage. Although loss of mitochondrial functions resulting from prolonged activation of the mitochondrial permeability transition (MPT) pore has been shown to play a significant role in perturbation of cellular bioenergetics and in cell death, the detailed mechanisms are still elusive. Enzymatic reactions linked to glycolysis, the tricarboxylic acid cycle, and mitochondrial respiration are dependent on the reduced or oxidized form of nicotinamide dinucleotide [NAD(H)] as a cofactor. Loss of mitochondrial NAD(+) resulting from MPT pore opening, although transient, allows detrimental depletion of mitochondrial and cellular NAD(+) pools by activated NAD(+) glycohydrolases. Poly(ADP-ribose) polymerase (PARP) is considered to be a major NAD(+) degrading enzyme, particularly under conditions of extensive DNA damage. We propose that CD38, a main cellular NAD(+) level regulator, can significantly contribute to NAD(+) catabolism. We discuss NAD(+) catabolic and NAD(+) synthesis pathways and their role in different strategies to prevent cellular NAD(+) degradation in brain, particularly following an ischemic insult. These therapeutic approaches are based on utilizing endogenous intermediates of NAD(+) metabolism that feed into the NAD(+) salvage pathway and also inhibit CD38 activity.

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Available from: Tibor Kristian, Jul 15, 2014
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    • "in an active consumption of ATP molecules in order to maintain the electrochemical gradient across the mitochondrial inner membrane. However, this consumption results in a bioenergetics crisis due to disruption in the equilibrium and finally results in programmed necrosis (Kristian et al., 2011;Oka, Hsu, & Sadoshima, 2012). Indeed NAD + consumption due to PARP hyperactivation has been purposed to block glycolysis and lead to metabolic breakdown, an effect that was increased by consumption as a result of ATPdependent NAD + synthesis (Virag, Robaszkiewicz, Rodriguez-Vargas, & Oliver, 2013). "
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    • "Activation of CD38 can lead to rapid and almost complete tissue NAD + depletion (Balan, et al., 2010). A prolonged MPT results not only in dissipation of the mitochondrial electrochemical hydrogen ion gradient and swelling of mitochondria but also depletion of pyridine nucleotides from the matrix (Di Lisa & Ziegler, 2001), however, significant loss of matrix pyridine nucleotides can lead to inhibition of mitochondrial respiration but without irreversible damage to the respiratory complexes or mitochondrial membranes (Kristian, et al., 2011). It was proposed, that once the cellular CD38 enzymatic pool is saturated, cytosolic NAD + concentrations rise to a level that permits efflux into extracellular space where NAD + becomes to be the substrate for surfaceexpressed CD38 acting as autocrine or paracrine regulator of Ca 2+ signaling. "

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