title: Age-related hearing loss in C57BL/6J mice is mediated by Bak-dependent mitochondrial apoptosis.
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 alpha-lipoic acid and coenzyme Q(10) 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.
authors.affiliation: Department of Genetics and Medical Genetics, Veterans Administration Hospital, Geriatric Research Education and Clinical Center, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Someya
authors.forename: Jinze
authors.initials: J
authors.lastname: Xu
authors.forename: Kenji
authors.initials: K
authors.lastname: Kondo
authors.forename: Dalian
authors.initials: D
authors.lastname: Ding
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Salvi
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yamasoba
authors.forename: Peter S
authors.initials: PS
authors.lastname: Rabinovitch
authors.forename: Richard
authors.initials: R
authors.lastname: Weindruch
authors.forename: Christiaan
authors.initials: C
authors.lastname: Leeuwenburgh
authors.forename: Masaru
authors.initials: M
authors.lastname: Tanokura
authors.forename: Tomas A
authors.initials: TA
authors.lastname: Prolla
mesh_terms: D000367:Age Factors; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D003051:Cochlea / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D011304:Presbycusis / Q000235:genetics* / Q000473:pathology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000975:Antioxidants; C494773:Bak1 protein, mouse; D050998:bcl-2 Homologous Antagonist-Killer Protein