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

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

Research output: Contribution to journalArticle

66 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)69-85
Number of pages17
JournalCell Reports
Volume17
Issue number1
DOIs
Publication statusPublished - 2016 Sep 27

Keywords

  • NAD
  • metabolism
  • mitochondria
  • neurodegeneration
  • photoreceptor
  • retina
  • sirtuins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'NAMPT-Mediated NAD<sup>+</sup> Biosynthesis Is Essential for Vision In Mice'. Together they form a unique fingerprint.

  • Cite this

    Lin, J. B., Kubota, S., Ban, N., Yoshida, M., Santeford, A., Sene, A., Nakamura, R., Zapata, N., Kubota, M., Tsubota, K., Yoshino, J., Imai, S. I., & Apte, R. S. (2016). NAMPT-Mediated NAD+ Biosynthesis Is Essential for Vision In Mice. Cell Reports, 17(1), 69-85. https://doi.org/10.1016/j.celrep.2016.08.073