Age-related hearing loss in C57BL/6J mice is mediated by Bak-dependent mitochondrial apoptosis
- Shinichi Someyaa,b,
- Jinze Xuc,
- Kenji Kondod,
- Dalian Dinge,
- Richard J. Salvie,
- Tatsuya Yamasobad,
- Peter S. Rabinovitchf,
- Richard Weindruchg,
- Christiaan Leeuwenburghc,
- Masaru Tanokurab and
- Tomas A. Prollaa,1
- Departments of aGenetics and Medical Genetics and
- gMedicine and Veterans Administration Hospital, Geriatric Research Education and Clinical Center, University of Wisconsin, Madison, WI 53706;
- Departments of bApplied Biological Chemistry,
- dOtolaryngology and Head and Neck Surgery, University of Tokyo, Tokyo 113-8657, Japan;
- cDepartment of Aging and Geriatrics, University of Florida, Gainesville, FL 32611;
- eCenter for Hearing and Deafness, University at Buffalo, Buffalo, NY 14214; and
- fDepartment of Pathology, University of Washington, Seattle, WA 98195
-
Edited by Barry Ganetzky, University of Wisconsin, Madison, WI, and approved September 25, 2009 (received for review August 10, 2009)
Abstract
Age-related hearing loss (AHL), known as presbycusis, is a universal feature of mammalian aging and is the most common sensory disorder in the elderly population. The molecular mechanisms underlying AHL are unknown, and currently there is no treatment for the disorder. Here we report that C57BL/6J mice with a deletion of the mitochondrial pro-apoptotic gene Bak exhibit reduced age-related apoptotic cell death of spiral ganglion neurons and hair cells in the cochlea, and prevention of AHL. Oxidative stress induces Bak expression in primary cochlear cells, and Bak deficiency prevents apoptotic cell death. Furthermore, a mitochondrially targeted catalase transgene suppresses Bak expression in the cochlea, reduces cochlear cell death, and prevents AHL. Oral supplementation with the mitochondrial antioxidants α-lipoic acid and coenzyme Q10 also suppresses Bak expression in the cochlea, reduces cochlear cell death, and prevents AHL. Thus, induction of a Bak-dependent mitochondrial apoptosis program in response to oxidative stress is a key mechanism of AHL in C57BL/6J mice.
Footnotes
- 1To whom correspondence should be addressed. E-mail: taprolla{at}wisc.edu
-
Author contributions: S.S. and T.A.P. designed research; S.S., J.X., and D.D. performed research; S.S., R.J.S., T.Y., P.S.R., R.W., C.L., M.T., and T.A.P. contributed new reagents/analytic tools; S.S., J.X., K.K., and D.D. analyzed data; and S.S. and T.A.P. wrote the paper.
-
Conflict of interest statement: S.S. and T.A.P. have filed a patent covering the general approach of Bak inhibition as a therapeutic approach for age-related hearing loss.
-
This article is a PNAS Direct Submission.
-
This article contains supporting information online at www.pnas.org/cgi/content/full/0908786106/DCSupplemental.
