A BAD link to mitochondrial cell death in the cochlea
of mice with noise-induced hearing loss.
Vicente-Torres
MA, Schacht J.
Kresge
Hearing Research Institute, University of Michigan, Ann Arbor, Michigan.
Acoustic overstimulation induces calcium overload
and activation of mitochondria-mediated cell death pathways in outer hair
cells (OHC) of the cochlea. However, it is not known whether these events
are interrelated or independent. We have recently reported that the
calcium-dependent phosphatase calcineurin
is activated in OHC following noise exposure and now postulate that calcium
overload triggers mitochondria-mediated death pathways through activation
of Bcl-2-associated death promoter (BAD) by calcineurin.
CBA/J mice were exposed to broadband noise (2-20 kHz), causing a permanent
threshold shift of about 40 dB at 12 and 20 kHz, corresponding to damage in
the middle and basal turns of the cochlea. Loss of OHC in the basal region
was evident in surface preparations. BAD immunostaining
in control animals had a cytoplasmic distribution
in the cells of the organ of Corti. Five hours
after acoustic overstimulation, mitochondria and
BAD redistributed to the perinuclear region of
OHC in the basal and middle turns but not in the apical turn. The nonapoptotic phospho-BAD (Ser
112) was up-regulated in cells undamaged by noise
(supporting cells and inner hair cells) but not in OHC. These data
establish a connection between calcium overload and mitochondria-mediated
death pathways in OHC and also suggest a dual role for BAD. The
translocation of BAD to the mitochondria in degenerating cells is
indicative of the activation of its proapoptotic
capacity, whereas up-regulation of phospho-BAD is
consistent with a nonapoptotic role of BAD in
less vulnerable cells. (c) 2006 Wiley-Liss, Inc.
PMID: 16521126 [PubMed - as supplied by publisher]
Inactivation of the Akt
Survival Pathway during Photoreceptor Apoptosis in the Retinal Degeneration
Mouse.
Jomary
C, Cullen J, Jones SE.
Retinitis Pigmentosa Research Unit, The Rayne
Institute, Wolfson Centre for Age-Related
Diseases, School of Biomedical and Health Sciences, King's College London,
St. Thomas' Hospital, London, United Kingdom.
PURPOSE: Previous work has indicated that the serine-threonine
protein kinase Akt is a
general mediator of cellular survival signals and that loss of Akt-mediated signaling can lead to the activation of
apoptosis. This study was conducted to establish whether regulation of the Akt survival pathway mechanisms is implicated in the
induction of apoptosis during photoreceptor cell death in the rd mouse
model of retinal degeneration. METHODS: Quantitative Western blot analysis
and immunocytochemistry were used to examine the
activation status and localization of key components of the Akt signaling cascade (Akt,
BAD, Forkhead [FKHR], HSP27, mitogen-activated
protein (MAP) kinase kinase-3 and -6 (MKK3/6),
the tumor-suppressor phosphatase PTEN, and the cytoplasmic protein-tyrosine kinase
cSrc-p60), in the retina of the rd mouse in comparison with the control.
The time points examined spanned the period of photoreceptor degeneration.
RESULTS: In the period up to the peak of photoreceptor apoptosis at
postnatal day 15, dysregulation of the survival
pathway was identified at several levels, including deactivation of both Akt itself and its downstream
transcription factor target Forkhead (FKHR) and
activation of the upstream negative regulator PTEN. CONCLUSIONS: Taken in
conjunction with previous studies, the data support a model in which
photoreceptor cell death in the rd mouse is the result of combined
inactivation of the Akt survival pathway and the
activation of the two major apoptotic pathways.
PMID: 16565401 [PubMed - as supplied by
publisher]
Apoptosis
signaling in response to 
