title: Activation of SIRT3 by the NAD⁺ precursor nicotinamide riboside protects from noise-induced hearing loss.
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.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Weill Medical College, Cornell University, New York, NY 10065, USA. Electronic address: kevin_d_brown@med.unc.edu.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Brown
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Weill Medical College, Cornell University, New York, NY 10065, USA.
authors.forename: Sadia
authors.initials: S
authors.lastname: Maqsood
authors.affiliation: Gladstone Institutes, University of California, San Francisco, San Francisco, CA 94941, USA.
authors.forename: Jing-Yi
authors.initials: JY
authors.lastname: Huang
authors.affiliation: Gladstone Institutes, University of California, San Francisco, San Francisco, CA 94941, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Pharmacology, Weill Medical College, Cornell University, New York, NY 10065, USA.
authors.forename: William
authors.initials: W
authors.lastname: Harkcom
authors.affiliation: Department of Pharmacology, Weill Medical College, Cornell University, New York, NY 10065, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Weill Medical College, Cornell University, New York, NY 10065, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Sauve
authors.affiliation: Gladstone Institutes, University of California, San Francisco, San Francisco, CA 94941, USA. Electronic address: eric.verdin@gladstone.ucsf.edu.
authors.forename: Eric
authors.initials: E
authors.lastname: Verdin
authors.affiliation: Department of Pharmacology, Weill Medical College, Cornell University, New York, NY 10065, USA. Electronic address: srj2003@med.cornell.edu.
authors.forename: Samie R
authors.initials: SR
authors.lastname: Jaffrey
mesh_terms: D000818:Animals; D005260:Female; D006317:Hearing Loss, Noise-Induced / Q000188:drug therapy / Q000517:prevention & control*; D008297:Male; D051379:Mice; D009243:NAD / Q000627:therapeutic use*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011726:Pyridinium Compounds; D056566:Sirtuin 3 / Q000378:metabolism*
chemical_list: D011726:Pyridinium Compounds; C018613:nicotinamide-beta-riboside; D009243:NAD; D009536:Niacinamide; D056566:Sirtuin 3