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

Abstract

Photoreceptor death is the endpoint of many blinding diseases. Identifying unifying pathogenic mechanisms in these diseases may offer global approaches for facilitating photoreceptor survival. We found that rod or cone photoreceptor-specific deletion of nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in the major NAD(+) biosynthetic pathway beginning with nicotinamide, caused retinal degeneration. In both cases, we could rescue vision with nicotinamide mononucleotide (NMN). Significantly, retinal NAD(+) deficiency was an early feature of multiple mouse models of retinal dysfunction, including light-induced degeneration, streptozotocin-induced diabetic retinopathy, and age-associated dysfunction. Mechanistically, NAD(+) deficiency caused metabolic dysfunction and consequent photoreceptor death. We further demonstrate that the NAD(+)-dependent mitochondrial deacylases SIRT3 and SIRT5 play important roles in retinal homeostasis and that NAD(+) deficiency causes SIRT3 dysfunction. These findings demonstrate that NAD(+) biosynthesis is essential for vision, provide a foundation for future work to further clarify the mechanisms involved, and identify a unifying therapeutic target for diverse blinding diseases.

• Authors: Jonathan B Lin, Shunsuke Kubota, Norimitsu Ban, Mitsukuni Yoshida, Andrea Santeford, Abdoulaye Sene, Rei Nakamura, Nicole Zapata, Miyuki Kubota, Kazuo Tsubota, Jun Yoshino, Shin-Ichiro Imai, Rajendra S Apte
• Journal: Cell reports (Cell Rep) Vol. 17 Issue 1 Pg. 69-85 (09 27 2016) ISSN: 2211-1247 [Electronic] United States
• PMID: 27681422 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Cytokines
• SIRT5 protein, mouse
• Sirt3 protein, mouse
• NAD
• Nicotinamide Mononucleotide
• Streptozocin
• Nicotinamide Phosphoribosyltransferase
• nicotinamide phosphoribosyltransferase, mouse
• Sirtuin 3
• Sirtuins

Topics

• Animals
• Cell Death
• Cytokines (deficiency, genetics)
• Diabetic Retinopathy (chemically induced, genetics, metabolism, pathology)
• Gene Expression Regulation
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Mitochondria (metabolism, pathology)
• NAD (metabolism)
• Nicotinamide Mononucleotide (metabolism)
• Nicotinamide Phosphoribosyltransferase (deficiency, genetics)
• Retinal Degeneration (genetics, metabolism, pathology)
• Retinal Rod Photoreceptor Cells (metabolism, pathology)
• Signal Transduction
• Sirtuin 3 (genetics, metabolism)
• Sirtuins (genetics, metabolism)
• Streptozocin
• Vision, Ocular (physiology)