Age-related hearing loss in C57BL/6J mice is mediated by Bak-dependent mitochondrial apoptosis.
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.
Someya
Shinichi
S
Department of Genetics and Medical Genetics, Veterans Administration Hospital, Geriatric Research Education and Clinical Center, University of Wisconsin, Madison, WI 53706, USA.
Xu
Jinze
J
Kondo
Kenji
K
Ding
Dalian
D
Salvi
Richard J
RJ
Yamasoba
Tatsuya
T
Rabinovitch
Peter S
PS
Weindruch
Richard
R
Leeuwenburgh
Christiaan
C
Tanokura
Masaru
M
Prolla
Tomas A
TA
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
D000975:Antioxidants; C494773:Bak1 protein, mouse; D050998:bcl-2 Homologous Antagonist-Killer Protein