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GM1-ganglioside accumulation at the mitochondria-associated ER membranes links ER stress to Ca(2+)-dependent mitochondrial apoptosis.
[gm1 gangliosidosis]
Mitochondria-associated
ER
membranes
,
or
MAMs
,
define
the
sites
of
endoplasmic
reticulum
/
mitochondria
juxtaposition
that
control
Ca
(
2
+
)
flux
between
these
organelles
.
We
found
that
in
a
mouse
model
of
the
human
lysosomal
storage
disease
GM
1
-
gangliosidosis
,
GM
1
-
ganglioside
accumulates
in
the
glycosphingolipid-enriched
microdomain
(
GEM
)
fractions
of
MAMs
,
where
it
interacts
with
the
phosphorylated
form
of
IP
3
receptor-
1
,
influencing
the
activity
of
this
channel
.
Ca
(
2
+
)
depleted
from
the
ER
is
then
taken
up
by
the
mitochondria
,
leading
to
Ca
(
2
+
)
overload
in
this
organelle
.
The
latter
induces
mitochondrial
membrane
permeabilization
(
MMP
)
,
opening
of
the
permeability
transition
pore
,
and
activation
of
the
mitochondrial
apoptotic
pathway
.
This
study
identifies
the
GEMs
as
the
sites
of
Ca
(
2
+
)
diffusion
between
the
ER
and
the
mitochondria
.
We
propose
a
new
mechanism
of
Ca
(
2
+
)
-
mediated
apoptotic
signaling
whereby
GM
1
accumulation
at
the
GEMs
alters
Ca
(
2
+
)
dynamics
and
acts
as
a
molecular
effector
of
both
ER
stress-induced
and
mitochondria-mediated
apoptosis
of
neuronal
cells
.
