NAMPT-Mediated NAD(+) Biosynthesis Is Essential for Vision In Mice.
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.
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA; Neuroscience Graduate Program, Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.
Jonathan B
JB
Lin
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.
Shunsuke
S
Kubota
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.
Norimitsu
N
Ban
Neuroscience Graduate Program, Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Mitsukuni
M
Yoshida
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.
Andrea
A
Santeford
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.
Abdoulaye
A
Sene
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.
Rei
R
Nakamura
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.
Nicole
N
Zapata
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.
Miyuki
M
Kubota
Department of Ophthalmology, Keio University School of Medicine, Tokyo 160-8582, Japan.
Kazuo
K
Tsubota
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Jun
J
Yoshino
Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: imaishin@wustl.edu.
Shin-Ichiro
SI
Imai
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: apte@vision.wustl.edu.
Rajendra S
RS
Apte
D000818:Animals; D016923:Cell Death; D016207:Cytokines / Q000172:deficiency / Q000235:genetics*; D003930:Diabetic Retinopathy / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009243:NAD / Q000378:metabolism*; D009537:Nicotinamide Mononucleotide / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000172:deficiency / Q000235:genetics*; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism; D013311:Streptozocin; D014785:Vision, Ocular / Q000502:physiology
D016207:Cytokines; C542554:SIRT5 protein, mouse; C525046:Sirt3 protein, mouse; D009243:NAD; D009537:Nicotinamide Mononucleotide; D013311:Streptozocin; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse; D056566:Sirtuin 3; D037761:Sirtuins
NAD(+); metabolism; mitochondria; neurodegeneration; photoreceptor; retina; sirtuins
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