Activation of SIRT3 by the NAD⁺ precursor nicotinamide riboside protects from noise-induced hearing loss

Cell Metab. 2014 Dec 2;20(6):1059-68. doi: 10.1016/j.cmet.2014.11.003.

Abstract

Intense noise exposure causes hearing loss by inducing degeneration of spiral ganglia neurites that innervate cochlear hair cells. Nicotinamide adenine dinucleotide (NAD(+)) exhibits axon-protective effects in cultured neurons; however, its ability to block degeneration in vivo has been difficult to establish due to its poor cell permeability and serum instability. Here, we describe a strategy to increase cochlear NAD(+) levels in mice by administering nicotinamide riboside (NR), a recently described NAD(+) precursor. We find that administration of NR, even after noise exposure, prevents noise-induced hearing loss (NIHL) and spiral ganglia neurite degeneration. These effects are mediated by the NAD(+)-dependent mitochondrial sirtuin, SIRT3, since SIRT3-overexpressing mice are resistant to NIHL and SIRT3 deletion abrogates the protective effects of NR and expression of NAD(+) biosynthetic enzymes. These findings reveal that administration of NR activates a NAD(+)-SIRT3 pathway that reduces neurite degeneration caused by noise exposure.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Hearing Loss, Noise-Induced / drug therapy
  • Hearing Loss, Noise-Induced / prevention & control*
  • Male
  • Mice
  • NAD / therapeutic use*
  • Niacinamide / analogs & derivatives*
  • Niacinamide / therapeutic use
  • Sirtuin 3 / metabolism*

Substances

  • nicotinamide-beta-riboside
  • NAD
  • Niacinamide
  • Sirtuin 3