NAD
            <sup>+</sup>
            acts on mitochondrial SirT3 to prevent axonal caspase activation and axonal degeneration

Magnifico, Sébastien; Saias, Laure; Deleglise, Bérangère; Duplus, Eric; Kilinc, Devrim; Miquel, Marie‐Christine; Viovy, Jean‐Louis; Brugg, Bernard; Peyrin, Jean‐Michel

doi:10.1096/fj.13-229781

Cited by 46 publications

(49 citation statements)

References 59 publications

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“…ARTICLE signalling molecules, such as the NAD þ signalling pathway, which controls axonal fate after local insults 42,43 . Similar to the findings reported here, NAD þ protects axons, but not the soma, upon global and/or local insults 19,44 .…”

Section: Discussionsupporting

confidence: 89%

“…Consistent with our previous findings [18][19][20] , we observed that direct somatic application of rotenone, a mitochondria complex I targeting toxin, led to rapid (o4 h) and massive cell death and axonal degeneration, which was moderately but consistently reduced by BDV infection ( Supplementary Fig. 1).…”

Section: Bdv Protects From Rotenone-induced Axonal Fragmentationsupporting

confidence: 91%

“…Microfluidic chips were prepared as described elsewhere 18,19 . In brief, culture chambers were moulded with polydimethylsiloxane (Sylgard 184, Dow Corning; 9:1 ratio with curing agent), which was poured into resin SU-8 silicon masters having a complementary positive relief pattern of the cell culture compartments and microchannels.…”

Section: Methodsmentioning

confidence: 99%

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A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson’s disease

et al. 2014

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Mitochondrial dysfunction is a common feature of many neurodegenerative disorders, notably Parkinson's disease. Consequently, agents that protect mitochondria have strong therapeutic potential. Here, we sought to divert the natural strategy used by Borna disease virus (BDV) to replicate in neurons without causing cell death. We show that the BDV X protein has strong axoprotective properties, thereby protecting neurons from degeneration both in tissue culture and in an animal model of Parkinson's disease, even when expressed alone outside of the viral context. We also show that intranasal administration of a cellpermeable peptide derived from the X protein is neuroprotective. We establish that both the X protein and the X-derived peptide act by buffering mitochondrial damage and inducing enhanced mitochondrial filamentation. Our results open the way to novel therapies for neurodegenerative diseases by targeting mitochondrial dynamics and thus preventing the earliest steps of neurodegenerative processes in axons.

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Section: Discussionsupporting

confidence: 89%

Section: Bdv Protects From Rotenone-induced Axonal Fragmentationsupporting

confidence: 91%

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A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson’s disease

et al. 2014

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“…Several groups have shown that NAD + can delay axon degeneration (4,9). Although the precise mechanisms by which NAD + delays axon degeneration are not known, a recent study suggests a possible role for SIRT3 (55). This earlier study showed that overexpression of SIRT3 delayed axon degeneration in an excitotoxic model.…”

Section: Discussionmentioning

confidence: 91%

NAD ⁺ and SIRT3 control microtubule dynamics and reduce susceptibility to antimicrotubule agents

Harkcom¹,

Ghosh²,

Sung³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Nicotinamide adenine dinucleotide (NAD + ) is an endogenous enzyme cofactor and cosubstrate that has effects on diverse cellular and physiologic processes, including reactive oxygen species generation, mitochondrial function, apoptosis, and axonal degeneration. A major goal is to identify the NAD + -regulated cellular pathways that may mediate these effects. Here we show that the dynamic assembly and disassembly of microtubules is markedly altered by NAD + . Furthermore, we show that the disassembly of microtubule polymers elicited by microtubule depolymerizing agents is blocked by increasing intracellular NAD + levels. We find that these effects of NAD + are mediated by the activation of the mitochondrial sirtuin sirtuin-3 (SIRT3). Overexpression of SIRT3 prevents microtubule disassembly and apoptosis elicited by antimicrotubule agents and knockdown of SIRT3 prevents the protective effects of NAD + on microtubule polymers. Taken together, these data demonstrate that NAD + and SIRT3 regulate microtubule polymerization and the efficacy of antimicrotubule agents.N icotinamide adenine dinucleotide (NAD + ) is an endogenous dinucleotide that is present in the cytosol, nucleus, and mitochondria. Athough it serves an important role as a redox cofactor in metabolism, NAD + is also a substrate for several families of enzymes, including the poly(ADP ribose) polymerases and the sirtuin deacetylase enzymes (reviewed in refs. 1 and 2). The level of intracellular NAD + is regulated by many factors, including diet and energy status (3), axonal injury (4), DNA damage (5), and certain disease states (6), suggesting that NAD + -dependent signaling is dynamically modulated in diverse contexts.NAD + -dependent signaling can be induced by treatment of cells with exogenous NAD + , which increases intracellular NAD + levels and results in diverse effects in cells and animals. These effects include enhanced oxygen consumption and ATP production (7), as well as protection from genotoxic stress and apoptosis (3). Mice treated with nicotinamide riboside, a NAD + precursor that is metabolized into NAD + , have enhanced oxidative metabolism, increased insulin sensitivity, and protection from high-fat diet-induced obesity (8). These results demonstrate that NAD + -dependent pathways can enhance metabolic function and improve a variety of disease phenotypes.An NAD + -regulated pathway also inhibits axonal degeneration elicited by axonal transection (4). Treatment of axons with 5-20 mM NAD + markedly delays the axon degenerative process (9). Additionally, animals that express the Wallerian degeneration slow (Wld S ) protein, a fusion of the NAD + biosynthetic enzyme Nicotinamide mononucleotide adenylyl transferase 1 and Ube4a, exhibit markedly delayed degeneration of the distal axonal fragment after axonal transection (10), and expression of Wld S mitigates disease phenotypes in several neurodegenerative disease models (11)(12)(13)(14). Thus, understanding the intracellular pathways regulated by NAD + may be important for understanding the pa...

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“…58 Furthermore, axonal degeneration was prevented by NAD + via mitochondrial SIRT3 rather than SIRT1. 59 It is worth to mention that mechanisms of neuronal death and axonal degeneration often differ. For instance, the Wlds protein has no effect on survival of the neuronal soma.…”

Section: Discussionmentioning

confidence: 99%

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

et al. 2015

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Oxidative stress and mitochondrial failure are prominent factors in the axonal degeneration process. In this study, we demonstrate that sirtuin 1 (SIRT1), a key regulator of the mitochondrial function, is impaired in the axonopathy and peroxisomal disease X-linked adrenoleukodystrophy (X-ALD). We have restored SIRT1 activity using a dual strategy of resveratrol treatment or by the moderate transgenic overexpression of SIRT1 in a X-ALD mouse model. Both strategies normalized redox homeostasis, mitochondrial respiration, bioenergetic failure, axonal degeneration and associated locomotor disabilities in the X-ALD mice. These results indicate that the reactivation of SIRT1 may be a valuable strategy to treat X-ALD and other axonopathies in which the control of redox and energetic homeostasis is impaired. Cell Death and Differentiation (2015) 22, 1742-1753 doi:10.1038/cdd.2015; published online 27 March 2015Sirtuins are highly conserved NAD + -dependent deacetylases with a critical impact on metabolic adaptive responses. In mammals, among the seven members of the sirtuin family (SIRT1-SIRT7), SIRT1 has been the most extensively characterized. 1 SIRT1 promotes the generation of new mitochondria through the activation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), which orchestrates the mitochondrial biogenesis program through the transcriptional activation of nuclear respiratory factors (NRF-1 and NRF-2) and mitochondrial transcription factor A (TFAM). 2 SIRT1 activity is finely regulated not only by gene expression and protein levels but also by posttranslational modifications, its oligomeric status, the interaction with the DBC1 and AROS proteins, and the levels of NAD + /NADH/NAM. 3 In addition, SIRT1 activity is modulated by several synthetic or natural molecules such as the polyphenol resveratrol (3,4',5-trihydroxystilbene: RSV). 4 The activation of SIRT1 by transgenic overexpression or pharmacologically with RSV has been shown to prevent the pathology in diseases commonly associated with mitochondrial dysfunction such as the metabolic syndrome and neurodegenerative disorders, 1,5,6 albeit recent findings cast doubts on the universal validity of the results. 7,8 Although prominent axonal pathology often precedes cell body loss in many neurodegenerative diseases, 9 the potential of SIRT1 activation in axonal degeneration has not been addressed in depth. In this work, we take advantage of the cellular and animal models of the rare monogenic neurodegenerative disease named X-linked adrenoleukodystrophy (X-ALD, (McKusick No.300100)) to evaluate the impact of SIRT1 function on axonal degeneration. X-ALD is the most prevalent peroxisomal disorder (minimum incidence 1:17 000 newborns), characterized by brain inflammatory demyelination and/or axonopathy of long tracts in spinal cords, adrenal insufficiency and a pathognomonic accumulation of very longchain fatty acids (VLCFA) in plasma and tissues, in particular hexacosanoic acid (C26:0). 10,11 The disease phenotypes range from adrenal ...

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NAD ⁺ acts on mitochondrial SirT3 to prevent axonal caspase activation and axonal degeneration

Cited by 46 publications

References 59 publications

A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson’s disease

A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson’s disease

NAD ⁺ and SIRT3 control microtubule dynamics and reduce susceptibility to antimicrotubule agents

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

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NAD + acts on mitochondrial SirT3 to prevent axonal caspase activation and axonal degeneration

Cited by 46 publications

References 59 publications

A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson’s disease

A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson’s disease

NAD + and SIRT3 control microtubule dynamics and reduce susceptibility to antimicrotubule agents

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

Contact Info

Product

Resources

About

NAD ⁺ acts on mitochondrial SirT3 to prevent axonal caspase activation and axonal degeneration

NAD ⁺ and SIRT3 control microtubule dynamics and reduce susceptibility to antimicrotubule agents