NAMPT-Mediated NAD+ Biosynthesis Is Essential for Vision In Mice

Lin, Jonathan B.; Kubota, Shunsuke; Ban, Norimitsu; Yoshida, Mitsukuni; Santeford, Andrea; Sène, Abdoulaye; Nakamura, Rei; Zapata, Nicole; Kubota, Miyuki; Tsubota, Kazuo; Yoshino, Jun; Imai, Shoichi; Apte, Rajendra S.

doi:10.1016/j.celrep.2016.08.073

Cited by 158 publications

(205 citation statements)

References 75 publications

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“…These findings suggest that these sirtuins are individually dispensable under basal conditions. These findings are important, as we previously demonstrated that NAMPT-mediated NAD + biosyn-thesis is essential for retinal function and that SIRT3/SIRT5 may play important roles in NAD + -dependent retinal homeostasis under conditions of stress (Lin et al 2016). These results expand on our previous findings and clarify the role of various sirtuin family members in retinal survival and function.…”

Section: Discussionmentioning

confidence: 86%

“…We examined multiple mice per genotype and present representative images. To assess retinal function, we performed electroretinography (ERG) with the UTAS-E3000 Visual Electrodiagnostic System running EM for Windows (LKC Technologies, Gaithersburg, MD), as described previously (Lin et al 2016), testing at least three mice per genotype. For statistical analysis of the ERG data, we used GraphPad Prism version 5.0f (La Jolla, CA) to perform a mixed two-way ANOVA (within-subjects factor, flash intensity; between-subjects factor, genotype).…”

Section: Methodsmentioning

confidence: 99%

“…The sirtuin family includes numerous members, which localize to unique subcellular compartments: SIRT1 and SIRT2 are present in the nucleus and the cytoplasm (North and Verdin 2007; Tanno et al 2007); SIRT6 is exclusively nuclear (Liszt et al 2005); and SIRT3, SIRT4, and SIRT5 are present in the mitochondria (Schwer et al 2002; Michishita et al 2005). We recently demonstrated that NAMPT-mediated NAD + biosynthesis is essential for photoreceptor survival and vision and that SIRT3 and SIRT5 play important roles in retinal homeostasis (Lin et al 2016). However, whether the other mitochondrial sirtuin SIRT4 and the nuclear/cytoplasmic sirtuins, SIRT1, SIRT2, and SIRT6, play important roles in retinal function under baseline conditions has not been adequately explored.…”

Section: Introductionmentioning

confidence: 99%

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Role of Sirtuins in Retinal Function Under Basal Conditions

Lin

Kubota

Mostoslavsky

et al. 2018

Retinal Degenerative Diseases

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Sirtuins are NAD+-dependent enzymes that govern cellular homeostasis by regulating the acylation status of their diverse target proteins. We recently demonstrated that both rod and cone photoreceptors rely on NAMPT-mediated NAD+ biosynthesis to meet their energetic requirements. Moreover, we found that this NAD+-dependent retinal homeostasis relies, in part, on maintenance of optimal activity of the mitochondrial sirtuins and of SIRT3 in particular. Nonetheless, it is unknown whether other sirtuin family members also play important roles in retinal homeostasis. Our results suggest that SIRT1, SIRT2, SIRT4, and SIRT6 are dispensable for retinal survival at baseline, as individual deletion of each of these sirtuins does not cause retinal degeneration by fundus biomicroscopy or retinal dysfunction by ERG. These findings have significant implications and inform future studies investigating the mechanisms underlying the central role of NAD+ biosyn-thesis in retinal survival and function.

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Section: Discussionmentioning

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role of Sirtuins in Retinal Function Under Basal Conditions

Lin

Kubota

Mostoslavsky

et al. 2018

Retinal Degenerative Diseases

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“…Furthermore, P7C3, a pro-neurogenic putative NAMPT activator (Pieper et al, 2010; Wang et al, 2014), is neuroprotective in animal models of Parkinson’s Disease and ALS (De Jesus-Cortes et al, 2012; Tesla et al, 2012). NAD-boosting regimens prevent and in some cases can reverse neuronal degeneration associated with hearing loss, prion toxicity, retinal damage, traumatic brain injury (TBI), and peripheral neuropathy (Brown et al, 2014; Dutca et al, 2014; Hamity et al, 2017; Lin et al, 2016; Vaur et al, 2017; Yin et al, 2014; Zhou et al, 2015). …”

Section: Effects Of Nad+ Boosters On Physiology and Health In Mouse Mmentioning

confidence: 99%

Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence

2018

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Nicotinamide adenine dinucleotide (NAD), the cell's hydrogen carrier for redox enzymes, is well known for its role in redox reactions. More recently, it has emerged as a signaling molecule. By modulating NAD-sensing enzymes, NAD controls hundreds of key processes from energy metabolism to cell survival, rising and falling depending on food intake, exercise, and the time of day. NAD levels steadily decline with age, resulting in altered metabolism and increased disease susceptibility. Restoration of NAD levels in old or diseased animals can promote health and extend lifespan, prompting a search for safe and efficacious NAD-boosting molecules that hold the promise of increasing the body's resilience, not just to one disease, but to many, thereby extending healthy human lifespan.

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“…This is also true for NR, as NRKs are rate limiting in its conversion to NMN. Although administration of NMN protects from retinal photoreceptor degenerations induced by NAMPT deficiency or light exposure 102 , potential accumulation of NMN may be detrimental for glaucoma as NMN can participate in axon degeneration 103 (axon injury and activation of axon intrinsic degeneration pathways are central in glaucoma). Thus NAM may have better efficacy than NMN in glaucoma.…”

Section: Choice Of Nad Precursor and Safetymentioning

confidence: 99%

Glaucoma as a Metabolic Optic Neuropathy: Making the Case for Nicotinamide Treatment in Glaucoma

Williams

Harder

John

2017

Journal of Glaucoma

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Mitochondrial dysfunction may be an important, if not essential, component of human glaucoma. Using transcriptomics followed by molecular and neurobiological techniques, we have recently demonstrated that mitochondrial dysfunction within retinal ganglion cells is an early feature in the DBA/2J mouse model of inherited glaucoma. Guided by these findings, we discovered that the retinal level of nicotinamide adenine dinucleotide (NAD, a key molecule for mitochondrial health) declines in an age-dependent manner. We hypothesized that this decline in NAD renders retinal ganglion cells susceptible to damage during periods of elevated intraocular pressure. To replete NAD levels in this glaucoma, we administered nicotinamide (the amide of vitamin B3). At the lowest dose tested, nicotinamide robustly protected from glaucoma (~70% of eyes had no detectable glaucomatous neurodegeneration). At this dose, nicotinamide had no influence on intraocular pressure and so its affect was neuroprotective. At the highest dose tested, 93% of eyes had no detectable glaucoma. This represents a ~10-fold decrease in the risk of developing glaucoma. At this dose, intraocular pressure still became elevated but there was a reduction in the degree of elevation showing an additional benefit. Thus, nicotinamide is unexpectedly potent at preventing this glaucoma and is an attractive option for glaucoma therapeutics. Our findings demonstrate the promise for both preventing and treating glaucoma via interventions that bolster metabolism during increasing age and during periods of elevated intraocular pressure. Nicotinamide prevents age-related declines in NAD (a decline that occurs in different genetic contexts and species). NAD precursors are reported to protect from a variety of neurodegenerative conditions. Thus, nicotinamide may provide a much needed neuroprotective treatment against human glaucoma. This manuscript summarizes human data implicating mitochondria in glaucoma, and argues for studies to further assess the safety and efficacy of nicotinamide in human glaucoma care.

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NAMPT-Mediated NAD+ Biosynthesis Is Essential for Vision In Mice

Cited by 158 publications

References 75 publications

Role of Sirtuins in Retinal Function Under Basal Conditions

Role of Sirtuins in Retinal Function Under Basal Conditions

Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence

Glaucoma as a Metabolic Optic Neuropathy: Making the Case for Nicotinamide Treatment in Glaucoma

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