Age-related hearing loss in C57BL/6J mice is mediated by Bak-dependent mitochondrial apoptosis

Edited by Barry Ganetzky, University of Wisconsin, Madison, WI, and approved September 25, 2009
November 17, 2009
106 (46) 19432-19437

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.

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Acknowledgments.

We thank J. M. Vann and K. Papez for technical assistance, and S. Kinoshita for histological processing. This research was supported by National Institutes of Health grants AG021905 (to T.A.P.), AG189222 (to R.W.), AG17994 (to C.L.), and AG21042 (to C.L.); the National Projects on Protein Structural and Functional Analyses from the Ministry of Education, Culture, Sports, Science, and Technologies of Japan; and Marine Bio Foundation.

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 106 | No. 46
November 17, 2009
PubMed: 19901338

Classifications

Submission history

Received: August 10, 2009
Published online: November 17, 2009
Published in issue: November 17, 2009

Keywords

  1. aging
  2. antioxidant
  3. cochlea
  4. oxidative stress
  5. presbycusis

Acknowledgments

We thank J. M. Vann and K. Papez for technical assistance, and S. Kinoshita for histological processing. This research was supported by National Institutes of Health grants AG021905 (to T.A.P.), AG189222 (to R.W.), AG17994 (to C.L.), and AG21042 (to C.L.); the National Projects on Protein Structural and Functional Analyses from the Ministry of Education, Culture, Sports, Science, and Technologies of Japan; and Marine Bio Foundation.

Notes

This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0908786106/DCSupplemental.

Authors

Affiliations

Shinichi Someya
Departments of aGenetics and Medical Genetics and
Departments of bApplied Biological Chemistry,
Jinze Xu
Department of Aging and Geriatrics, University of Florida, Gainesville, FL 32611;
Kenji Kondo
Otolaryngology and Head and Neck Surgery, University of Tokyo, Tokyo 113-8657, Japan;
Dalian Ding
Center for Hearing and Deafness, University at Buffalo, Buffalo, NY 14214; and
Richard J. Salvi
Center for Hearing and Deafness, University at Buffalo, Buffalo, NY 14214; and
Tatsuya Yamasoba
Otolaryngology and Head and Neck Surgery, University of Tokyo, Tokyo 113-8657, Japan;
Peter S. Rabinovitch
Department of Pathology, University of Washington, Seattle, WA 98195
Richard Weindruch
Medicine and Veterans Administration Hospital, Geriatric Research Education and Clinical Center, University of Wisconsin, Madison, WI 53706;
Christiaan Leeuwenburgh
Department of Aging and Geriatrics, University of Florida, Gainesville, FL 32611;
Masaru Tanokura
Departments of bApplied Biological Chemistry,
Tomas A. Prolla1 [email protected]
Departments of aGenetics and Medical Genetics and

Notes

1
To whom correspondence should be addressed. E-mail: [email protected]
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.

Competing Interests

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.

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    Age-related hearing loss in C57BL/6J mice is mediated by Bak-dependent mitochondrial apoptosis
    Proceedings of the National Academy of Sciences
    • Vol. 106
    • No. 46
    • pp. 19205-19629

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